Cephem intermediates

ABSTRACT

Alkoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetic acid compounds are intermediates for cephem compounds.

This application is a division of application Ser. No. 213,351, filedDec. 5, 1980, now U.S. Pat. No. 4,447,429, which in turn is a divisionof application Ser. No. 50,216, filed June 20, 1979, now U.S. Pat. No.4,268,509.

This invention relates to new cephem compounds. More particularly, itrelates to new 7-substituted-3-cephem-4-carboxylic acid andpharmaceutically acceptable salt thereof, which have antimicrobialactivities, and processes for preparation thereof, to intermediate forpreparing the same and processes for preparation thereof, and topharmaceutical composition comprising the same and methods of using thesame prophylactically and therapeutically for treatment of infectiousdiseases in human being and animals.

Accordingly, the objects of this invention are to provide:

new 7-substituted-3-cephem-4-carboxylic acid and pharmaceuticallyacceptable salt thereof, which exhibit excellent antimicrobialactivities against a wide variety of pathogenic microorganisms includingGram negative and Gram positive bacteria,

processes for preparation of the same,

pharmaceutical composition comprising one of the same as an activeingredient, and

a method of using the same prophylactically and therapeutically fortreatment of infectious diseases caused by pathogenic microorganisms inhuman being and animals; and further

intermediate to be used for preparation of pharmaceutically active7-substituted-3-cephem-4-carboxylic acid or pharmaceutically acceptablesalt thereof and processes for preparation thereof.

The object 7-substituted-3-cephem-4-carboxylic acid is novel and can berepresented by the following general formula (I). ##STR1## wherein R¹ isamino or a protected amino,

R² is lower alkyl,

R³ is hydrogen or lower alkyl,

R⁴ is hydrogen, acyloxy(lower)alkyl, acylthio(lower)alkyl or aheterocyclicthio(lower)alkyl which may be substituted with suitablesubstituent(s) and

R⁵ is carboxy or a protected carboxy.

According to the present invention, the object7-substituted-3-cephem-4-carboxylic acid (I) can be prepared by thefollowing processes. ##STR2## wherein

R¹, R², R³, R⁴ and R⁵ are each as defined above;

R^(5a) is a protected carboxy;

R^(4a) is a group which can be substituted by a group R^(4b) --S--wherein R^(4b) is acyl or a heterocyclic group which may be substitutedwith suitable substituent(s);

A is lower alkylene;

R^(4b) is as defined above;

R^(4c) is a heterocyclicthio(lower)alkyl substituted with protectedamino(lower)alkyl or protected amino; and

R^(4d) is a heterocyclicthio(lower)alkyl substituted withamino(lower)alkyl or amino.

Among the starting compounds of the present invention, the compound(III) is novel and can be prepared by the following preparations.##STR3## wherein R² is as defined above,

R⁶ is a protective group of carboxy,

M is an alkali metal,

R^(1a) is a protected amino and

R⁷ is lower alkyl.

In the object compound (I) and the starting compound (III), the partialstructure represented by the formula: ##STR4## is to be understood toinclude both of the geometrical structures represented by the formulae:##STR5## In this specification, with regard to all the compounds havingthe above mentioned partial structure, the compounds having thegeometrical structure shown by the formula (A) are referred to as "synisomer" and the compounds having the alternative one shown by theformula (A') as "anti isomer".

Regarding the object compound of the formula (I) and the startingcompound of the formula (III) as mentioned above, it is also to beunderstood that said object and starting compounds may includetautomeric isomers relating to their thiadiazolyl group. That is, incase that the group represented by the formula: ##STR6## (wherein R¹ isamino or a protected amino) in formula of said object and startingcompounds take the formula: ##STR7## (wherein R¹ is as defined above),said group of the formula: ##STR8## may be also alternativelyrepresented by its tautomeric formula: ##STR9## (wherein R^(1') is iminoor a protected imino). That is, both of the said group (B) and (B') maybe in the state of equilibrium as so-called tautomeric forms which canbe represented by the following equilibrium: ##STR10## (wherein R¹ andR^(1') are each as defined above).

In the present specification including claims and examples, the objectand starting compounds having said group are represented by using one ofthe expressions therefor, namely the formula: ##STR11## only for theconvenient sake.

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salts and may include an inorganic salt, forexample, a metal salt such as an alkali metal salt (e.g., sodium salt,potassium salt, etc.) and an alkaline earth metal salt (e.g., calciumsalt, magnesium salt, etc.), ammonium salt etc.; an organic salt, forexample, an organic amine salt (e.g., trimethylamine salt, triethylaminesalt, pyridine salt, procaine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylene-diamine salt, N-methylglucamine salt,diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)methane salt, phenylethylbenzylamine salt,dibenzylethylenediamine salt, etc.) etc.: an organic carboxylic orsulfonic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate,benzenesulfonate, toluenesulfonate, etc.); an inorganic acid salt (e.g.,hydrochloride, hydrobromide, sulfate, phosphate, etc.); a salt with abasic or acidic amino acid (e.g., arginine, aspartic acid, glutamicacid, lysine, etc.) and the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustration of the various definitions which thepresent invention intends to include within the scope thereof areexplained in detail as follows.

The term "lower" is used to intend a group having 1 to 6 carbon atom(s),unless otherwise provided.

Suitable protected amino may include an acylamino and amino groupsubstituted by a conventional proptective group other than the acylgroup, such as ar(lower)alkyl(e.g., benzyl, trityl, etc.)ar(lower)alkylidene(e.g., benzylidene, etc.), lower alkylidenesubstituted with lower alkoxycarbonyl or di(lower)alkylamino(e.g.,1-ethoxycarbonyl-2-propylidene, dimethylaminomethylene, etc.), phosphonoor the like.

Suitable protected imino may include an acylimino and imino groupsubstituted by a conventional protective group other than the acyl groupsuch as aforesaid ar(lower)alkyl or the like.

Suitable acyl and acyl moiety in the terms "acylamino", "acylimino","acyloxy(lower)alkyl" and "acylthio(lower)alkyl" may include carbamoyl,aliphatic acyl group and acyl group containing an aromatic orheterocyclic ring. And, suitable examples of the said acyl may be loweralkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, oxalyl, succinyl, pivaloyl, etc.), preferably one having 1to 4 carbon atom(s), more preferably one having 1 to 2 carbon atom(s);lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), preferably one having 3 to6 carbon atoms; lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl,propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.);arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g.,benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.);ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.);ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl,etc.); and the like.

The acyl and acyl moiety as stated above may have 1 to 3 suitablesubstituent(s) such as halogen (e.g., chlorine, bromine, iodine orfluorine), hydroxy, cyano, nitro, lower alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, etc.), lower alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, etc.), lower alkenyl (e.g., vinyl, allyl, etc.), aryl(e.g., phenyl, tolyl, etc.), or the like.

Suitable lower alkyl and lower alkyl moiety in the terms"acyloxy(lower)alkyl", "acylthio(lower)alkyl" and"heterocyclicthio(lower)alkyl" may include one having 1 to 6 carbonatom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, tert-pentyl, hexyl or the like, preferably onehaving 1 to 3 carbon atom(s).

Suitable protected carboxy may include esterified carboxy in which saidester may be the ones such as lower alkyl ester (e.g., methyl ester,ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester,1-cyclopropylethyl ester, etc.), wherein lower alkyl moiety may bepreferably one having 1 to 4 carbon atom(s); lower alkenyl ester (e.g.,vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynylester, propynyl ester, etc.); mono(or di or tri)-halo(lower)alkyl ester(e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); loweralkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethylester, 2-propionyloxyethyl ester, etc.); loweralkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethylester, etc.); ar(lower)alkyl ester, for example, phenyl(lower)alkylester which may be substituted with one or more suitable substituent(s)(e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester,phenethyl ester, trityl ester, diphenylmethyl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-ditertiarybutylbenzyl ester, etc.); aryl ester which mayhave one or more suitable substituent(s) (e.g., phenyl ester, tolylester, tertiarybutylphenyl ester, xylyl ester, mesityl ester, cumenylester, etc.), and the like.

Preferable example of protected carboxy may be lower alkoxycarbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.) having 2to 7 carbon atoms, preferably one having 2 to 5 carbon atoms andphenyl(lower)alkoxycarbonyl which may be substituted with nitro (e.g.,4-nitrobenzyloxycarbonyl, benzyloxycarbonyl,4-nitrophenethyloxycarbonyl, etc.).

Suitable heterocyclic group and heterocyclic moiety in the term "aheterocyclicthio(lower)alkyl" means saturated or unsaturated, monocyclicor polycyclic heterocyclic group containing at least one hetero-atomsuch as an oxygen, sulfur, nitrogen atom and the like. And, especiallypreferably heterocyclic group may be heterocyclic group such asunsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl,triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.; unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atom(s), for example,indolyl, isoindolyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl,dihydrotriazolopyridazinyl, etc.; unsaturated 3- to 8-memberedheteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;saturated 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl,etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.; unsaturated 3 to 8-membered heteromonocyclicgroup containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), forexample, thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc.; saturated 3 to8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3to 8-membered heteromonocyclic group containing a sulfur atom, forexample, thienyl, etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), forexample, benzothiazolyl, benzothiadiazolyl, etc. and the like;

wherein said heterocyclic group may be substituted with one or twosuitable substituent(s) such as lower alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), preferably onehaving 1 to 3 carbon atom(s); lower alkylthio (e.g., methylthio,ethylthio, propylthio, etc.); lower alkenyl (e.g., vinyl, allyl,butenyl, etc.), preferably one having 2 to 3 carbon atoms; loweralkenylthio (e.g., vinylthio, allylthio, butenylthio, etc.), preferablyone having 2 to 3 carbon atoms; aryl (e.g., phenyl, tolyl, etc.);halogen (e.g., chlorine, bromine, iodine or fluorine); amino;di(lower)alkylamino(lower)alkyl (e.g., dimethylaminomethyl,dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl,diethylaminobutyl, etc.); carboxy(lower)alkyl (e.g., carboxymethyl,carboxyethyl, carboxypropyl, etc.), preferably one having 2 to 4 carbonatoms; esterified carboxy(lower)alkyl wherein the esterified carboxymoiety is exemplified above; amino(lower)alkyl (e.g., aminomethyl,aminoethyl, aminopropyl, 1-aminomethylethyl, aminobutyl, etc.),preferably one having 1 to 3 carbon atom(s); protected amino(lower)alkylwherein the protected amino and lower alkyl moieties are each asexemplified above, preferably lower alkoxycarbonylamino(lower)alkyl(e.g., methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,t-butoxycarbonylaminomethyl, t-butoxycarbonylaminoethyl,t-butoxycarbonylaminopropyl, 1-t-butoxycarbonylaminomethylethyl, etc.),more preferably one having 3 to 9 carbon atoms, or loweralkanoylamino(lower)alkyl (e.g., acetylaminomethyl, acetylaminoethyl,acetylaminopropyl, 1-acetylaminomethylethyl, etc.), more preferably onehaving 2 to 5 carbon atoms; carboxy; esterified carboxy as exemplifiedabove, preferably lower alkoxycarbonyl, more preferably one having 2 to3 carbon atoms; lower alkoxy(lower)alkyl (e.g., methoxymethyl,methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, etc.),preferably one having 2 to 5 carbon atoms; hydroxy(lower)alkyl(e.g.,hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.),preferably one having 1 to 3 carbon atom(s); lower alkylthio(lower)alkyl(e.g., methylthiomethyl, methylthioethyl, methylthiopropyl,ethylthiomethyl, etc.), preferably one having 2 to 3 carbon atoms;sulfo(lower)alkyl (e.g., sulfomethyl, sulfoethyl, sulfopropyl,sulfobutyl, etc.), preferably one having 1 to 2 carbon atom(s);acyl(lower)alkyl wherein the acyl and lower alkyl moieties are each asexemplified above, preferably lower alkanesulfonyl(lower)alkyl (e.g.,mesylmethyl, mesylethyl, ethanesulfonylmethyl, etc.), more preferablyone having 2 to 3 carbon atoms; acylamino(lower)alkyl wherein the acyland lower alkyl moieties are each as exemplified above, preferably loweralkanesulfonylamino(lower)alkyl (e.g., mesylaminomethyl,mesylaminoethyl, mesylaminopropyl, ethanesulfonylaminomethyl, etc.),more preferably one having 2 to 3 carbon atoms; carboxy(lower)alkylthio(e.g., carboxymethylthio, carboxyethylthio, etc.), preferably one having2 to 3 carbon atoms; oxo; halo(lower)alkyl (e.g., chloromethyl,chloroethyl, dichloroethyl, trichloroethyl, trifluoromethyl,trichloromethyl, trifluoroethyl, etc.), preferably trihalo(lower)alkyl,more preferably one having 1 to 2 carbon atom(s); lower alkylamino(e.g., methylamino, ethylamino, propylamino, isopropylamino, etc.),preferably one having 1 to 2 carbon atom(s); protected amino asexemplified above; or the like.

Suitable lower alkylene may include straight or branched bivalentaliphatic hydrocarbon residue having 1 to 6 carbon atom(s), such asmethylene, ethylene, methylethylene, propylene, trimethylene,2-methyltrimethylene or the like, and preferably one having 1 to 4carbon atom(s), more preferably one having 1 to 2 carbon atom(s) and themost preferably one having 1 carbon atom.

Suitable protected amino(lower)alkyl, protected amino andamino(lower)alkyl being the substituent of aheterocyclicthio(lower)alkyl for R^(4c) and R^(4d) can be each referredto the ones as exemplified above.

Suitable protective group of carboxy may be referred to the onesexemplified as aforementioned ester moiety in the esterified carboxygroup. Preferable example of protective group of carboxy may be loweralkyl as mentioned above.

Suitable alkali metal may include sodium, potassium, lithium, etc.

Preferred embodiments of the object compound (I) are as follows.

Preferred embodiment of R¹ is amino, acylamino (more preferably loweralkanoylamino), di(lower)alkylamino(lower)alkylideneamino orphosphonoamino;

R² is lower alkyl;

R³ is hydrogen or lower alkyl;

R⁴ is hydrogen; acyloxy(lower)alkyl [more preferably loweralkanoyloxy(lower)alkyl or carbamoyloxy(lower)alkyl, most preferablylower alkanoyloxymethyl or carbamoyloxymethyl]; acylthio(lower)alkyl[more preferably lower alkanoylthio(lower)alkyl, most preferably loweralkanoylthiomethyl]; tetrazolylthio(lower)alkyl (more preferablytetrazolylthiomethyl) substituted with lower alkyl, lower alkenyl, loweralkoxy(lower)alkyl, lower alkylthio(lower)alkyl, hydroxy(lower)alkyl,amino(lower)alkyl, lower alkoxycarbonylamino(lower)alkyl, loweralkanoylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl,sulfo(lower)alkyl or carboxy(lower)alkyl; thiadiazolylthio(lower)alkyl(more preferably thiadiazolylthiomethyl) which may be substituted withlower alkyl, lower alkoxy(lower)alkyl, lower alkylthio(lower)alkyl,lower alkenylthio, carboxy, lower alkoxycarbonyl, hydroxy(lower)alkyl,amino(lower)alkyl, lower alkoxycarbonylamino(lower)alkyl, amino, loweralkylamino, halo(lower)alkyl, carboxy(lower)alkylthio, loweralkanesulfonyl(lower)alkyl, lower alkanesulfonylamino(lower)alkyl orcarboxy(lower)alkylthio; triazolylthio(lower)alkyl (more preferablytriazolylthiomethyl)substituted with lower alkyl, lower alkenyl or loweralkoxy(lower)alkyl; pyrazinylthio(lower)alkyl (more preferablypyrazinylthiomethyl); thiazolinylthio(lower)alkyl(more preferablythiazolinylthiomethyl); tetrazolopyridazinylthio(lower)alkyl (morepreferably tetrazolopyridazinylthiomethyl); ordihydrotriazolopyridazinylthio(lower)alkyl (more preferablydihydrotriazolopyridazinylthiomethyl) substituted with oxo andcarboxy(lower)alkyl;

and R⁵ is carboxy or phenyl(lower)alkoxycarbonyl substituted with nitro.

The processes for preparing the object compounds are explained indetails in the following.

PROCESS 1

The object compound (I) can be prepared by reacting the compound (II) orits reactive derivative at the amino group or a salt thereof with thecompound (III) or its reactive derivative at the carboxy group or a saltthereof.

Suitable reactive derivative at the amino group of the compound (II) mayinclude conventional reactive derivative used in amidation, for example,Schiff's base type imino or its tautomeric enamine type isomer formed bythe reaction of the compound (II) with a carbonyl compound; a silylderivative formed by the reaction of the compound (II) with a silylcompound such as bis(trimethylsilyl)acetamide, trimethylsilylacetamideor the like; a derivative formed by reaction of the compound (II) withphosphorus trichloride or phosgene, and the like.

Suitable salt of the compound (II) may include an acid addition saltsuch as an organic acid salt (e.g., acetate, maleate, tartrate,benzenesulfonate, toluenesulfonate, etc.) or an inorganic acid salt(e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); a metalsalt (e.g., sodium salt, potassium salt, calcium salt, magnesium salt,etc.); ammonium salt; an organic amine salt (e.g., triethylamine salt,dicyclohexylamine salt, etc.), and the like.

Suitable reactive derivative at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. The suitable example may be an acidchloride; an acid azide; a mixed acid anhydride with an acid such assubstituted phosphoric acid (e.g., dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphaticcarboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, acetic acid or trichloroacetic acid, etc.) oraromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acidanhydride; an activated amide with imidazole, dimethylpyrazole, triazoleor tetrazole; or an activated ester (e.g., cyanomethyl ester,methoxymethyl ester, dimethyliminomethyl [(CH₃)₂ N⁺ ═CH--]ester, vinylester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester,phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, or an ester withN,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide or1-hydroxy-6-chloro-1H-benzotriazole, and the like. These reactivederivatives can be optionally selected from them according to the kindof the compound (III) to be used.

The salts of the compound (III) may be salts with an inorganic base suchas an alkali metal salts (e.g., sodium or potassium salt), or analkaline earth metal salt (e.g., calcium or magnesium salt), a salt withan organic base such as trimethylamine, triethylamine, pyridine, a saltwith an acid (e.g., hydrochloric acid or hydrobromic acid) or the like.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which doesnot adversely influence to the reaction. Among these solvents,hydrophilic solvents may be used in a mixture with water.

When the compound (III) is used in free acid form or its salt form inthe reaction, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N-diethylcarbodiimide; N,N-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis(2-methylimidazole);pentamethylene-ketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene; ethyl polyphosphate;isopropyl polyphosphate; diethyl phosphorochloridite; phosphorusoxychloride; phosphorous trichloride; phosphorus pentachloride; thionylchloride; oxalyl chloride; triphenylphosphine;N-ethyl-7-hydroxybenzisoxazolium fluoroborate;N-ethyl-5-phenylisoxazolium-3'-sulfonate;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent, for example (chloromethylene)dimethylammoniumchloride produced by the reaction of dimethylformamide with thionylchloride or phosgene, a compound produced by the reaction ofdimethylformamide with phosphorus oxychloride, etc.; or the like.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal hydroxide, an alkali metalbicarbonate, alkali metal carbonate, alkali metal acetate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline as exemplifiedbelow, or the like. When the base or the condensing agent is in liquid,it can be used also as a solvent. The reaction temperature is notcritical, and the reaction is usually carried out under cooling or atambient temperature.

In the present reaction, a syn-isomer of the object compound (I) can beobtained preferably by conducting the reaction of the compound (II) witha synisomer of the starting compound (III).

In the present reaction, amino group for R¹ in the compound (III) may beconverted into a protected amino group to give the compound (I) whereinR¹ is a protected amino in the course of the reaction according toreaction conditions, and this case is also included within the scope ofthe present reaction.

PROCESS 2

The object compound (Ib) or a salt thereof can be prepared by subjectingthe compound (Ia) or a salt thereof to elimination reaction of theprotective group of carboxy.

Suitable salt of the compound (Ia) can be referred to the acid additionsalt exemplified for the compound (II).

The present reaction is carried out in accordance with a conventionalmethod such as hydrolysis, reduction or the like.

In case that the protective group is an ester, the protective group canbe eliminated by hydrolysis. Hydrolysis is preferably carried out in thepresence of a base or an acid. Suitable base may include an inorganicbase and an organic base such as an alkali metal (e.g., sodium,potassium, etc.), an alkaline earth metal (e.g., magnesium, calcium,etc.), the hydroxide or carbonate or bicarbonate thereof, trialkylamine(e.g., trimethylamine, triethylamine, etc.), picoline,1,5-diazabicyclo[4,3,0]none-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,8-diazabicyclo[5,4,0]undecene-7, or the like. Suitable acid mayinclude an organic acid (e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, etc.) and an inorganic acid (e.g., hydrochloricacid, hydrobromic acid, sulfuric acid, etc.).

The reaction is usually carried out in a solvent such as water, analcohol (e.g., methanol, ethanol, etc.), a mixture thereof or any othersolvent which does not adversely influence to the reaction. A liquidbase or acid can be also used as the solvent. The reaction temperatureis not critical and the reaction is usually carried out under cooling towarming.

Reduction can be applied preferably for elimination of the protectivegroup such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, or thelike. The reduction method applicable for the elimination reaction mayinclude, for example, reduction by using a combination of a metal (e.g.,zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g., chromouschloride, chromous acetate, etc.) and an organic or inorganic acid(e.g., acetic acid, propionic acid, hydrochloric acid, etc.); andconventional catalytic reduction in the presence of a conventionalmetallic catalyst (e.g., palladium-carbon, etc.).

PROCESS 3

The object compound (Id) or a salt thereof can be prepared by reactingthe compound (Ic) or a salt thereof with the compound (IV) or itsreactive derivative at the mercapto group.

Suitable salt of the compound (Ic) can be referred to the onesexemplified for the compound (II).

Suitable reactive derivative at the mercapto group of the compound (IV)may include a metal salt such as an alkali metal salt (e.g., sodiumsalt, potassium salt, etc.) or the like.

The present reaction may be carried out in a solvent such as water,phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride,ethylene chloride, dimethylformamide, methanol, ethanol, ether,tetrahydrofuran, dimethylsulfoxide, or any other organic solvent whichdoes not adversely affect the reaction, preferably in ones having strongpolarities. Among the solvents, hydrophilic solvents may be used in amixture with water. The reaction is preferably carried out in aroundneutral medium. When the compound (Ic) or the compound (IV) is used in afree form, the reaction is preferably conducted in the presence of abase, for example, inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkali metal bicarbonate, organic base such astrialkylamine, and the like. The reaction temperature is not critical,and the reaction is usually carried out at ambient temperature, underwarming or under slightly heating.

PROCESS 4

The object compound (If) or a salt thereof can be prepared by subjectingthe compound (Ie) or a salt thereof to elimination reaction of theprotective group of amino.

Suitable salt of the compound (Ie) may include a metal salt, ammoniumsalt, an organic amine salt and the like as aforementioned.

The present elimination reaction is carried out in accordance with aconventional method such as hydrolysis; reduction; a method by reactingthe compound (Ie) wherein the pretective group is acyl group withiminohalogenating agent and then with iminoetherifying agent, and, ifnecessary, subjecting the resulting compound to hydrolysis; or the like.The hydrolysis may include a method using an acid or base or hydrazineand the like. These methods may be selected depending on the kind of theprotective groups to be eliminated.

Among these methods, hydrolysis using an acid is one of the common andpreferable method for eliminating the protective group such assubstituted or unsubstituted alkoxycarbonyl (e.g., t-pentyloxycarbonyl,t-butoxycarbonyl, etc.), alkanoyl (e.g., formyl, etc.),cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarboxyl(e.g., benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.),substituted phenylthio, substituted aralkylidene, substitutedalkylidene, substituted cycloalkylidene, ar(lower)alkyl (e.g., benzyl,trityl, etc.) or the like.

Suitable acid may include an organic or an inorganic acid, for example,formic acid, trifluoroacetic acid, benzenesulfonic acid,p-toluenesulfonic acid, hydrochloric acid and the like, and preferableacid is, for example, formic acid, trifluoroacetic acid, hydrochloricacid, etc. The acid suitable for the reaction can be selected accordingto the kind of protective group to be eliminated. When the eliminationreaction is conducted with the acid, it can be carried out in thepresence or absence of a solvent. Suitable solvent may include aconventional organic solvent, water or a mixture thereof. Whentrifluoroacetic acid is used, the elimination reaction may preferably becarried out in the presence of anisole.

The hydrolysis using hydrazine is commonly applied for eliminating theprotective group, for example, succinyl or phthaloyl.

The hydrolysis with a base is preferably applied for eliminating acylgroup, for example, haloalkanoyl (e.g., dichloroacetyl, trifluoroacetyl,etc.) etc. Suitable base may include, for example, an inorganic basesuch as alkali metal hydroxide (e.g., sodium hydroxide, potassiumhydroxide, etc.), alkaline earth metal hydroxide (e.g., magnesiumhydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g.,sodium carbonate, potassium carbonate, etc.), alkaline earth metalcarbonate (e.g., magnesium carbonate, calcium carbonate, etc.), alkalimetal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate,etc.), alkali metal acetate (e.g., sodium acetate, potassium acetate,etc.), alkaline earth metal phosphate (e.g., magnesium phosphate,calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g.,disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), orthe like, and an organic base such as trialkylamine (e.g.,trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo[4,3,0]non-5-ene,1-4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]undecene-5- or thelike. The hydrolysis using a base is often carried out in water, aconventional organic solvent or a mixture thereof.

Among the protective group, the acyl group can be generally eliminatedby hydrolysis as mentioned above or by the other conventionalhydrolysis. In case that the acyl group is halogensubstituted-alkoxycarbonyl or 8-quinolyloxycarbonyl, they are eliminatedby treating with a heavy metal such as copper, zinc or the like.

The reductive elimination is generally applied for eliminating theprotective group, for example, haloalkoxycarbonyl (e.g.,trichloroethoxycarbonyl etc.), substituted or unsubstitutedaralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyletc.), 2-pyridylmethoxycarbonyl, etc. Suitable reduction may include,for example, reduction with an alkali metal borohydride (e.g., sodiumborohydride, etc.) and the like.

The reaction temperature is not critical and may be suitably selected inaccordance with the kind of the protective group of the amino group andthe elimination method as mentioned above, and the present reaction ispreferably carried out under a mild condition such as under cooling, atambient temperature or slightly elevated temperature.

The present reaction includes, within its scope, the cases that theprotected carboxy group for R⁵ is transformed into the free carboxygroup in the course of the elimination reaction as mentioned above or inthe post-treatment of the reaction mixture or reaction product.

The preparation for preparing the starting compound (III) are explainedbelow in detail.

PREPARATION (1)

The compound (VII) can be prepared by reacting the compound (V) or asalt thereof with halogenating agent and the compound (VI).

Suitable halogenating agent to be used in the present reaction mayinclude bromine, chlorine and the like.

The present reaction is preferably carried out in the presence of a basesuch as an inorganic base or an organic base, for example, alkali metalcarbonate, alkali metal alkoxide, trialkylamine or the like. The presentreaction is usually carried out in a solvent such as an alcohol (e.g.,methanol, ethanol, etc.) or any other solvent which does not adverselyaffect the reaction. The reaction temperature is not critical and thereaction is usually carried out under cooling or at ambient temperature.In this reaction, R⁶ of the compound (V) may be converted into otherprotective group of carboxy according to reaction conditions and kindsof the protective group and it is included within the scope of thepresent reaction.

PREPARATION (2)

The compound (VIII) can be prepared by subjecting the compound (VII) tointroduction reaction of the protective group of amino.

The present process can be carried out in a conventional manner and whenthe protective group of amino to be introduced into the amino group isacyl, the reaction can be carried out in substantially the same manneras that of Process 1. Accordingly, the detailed explanation therefor isto be referred to said Process 1.

PREPARATION (3)

The compound (X) can be prepared by reacting the compound (VIII) withthe compound (IX). This process is usually carried out in the presenceof base such as an alkali metal hydride (e.g., sodium hydride, potassiumhydride, etc.), an alkaline earth metal hydride (e.g., calcium hydride,etc.) and the like, and usually carried out in a solvent such asdimethylformamide or any other solvent which does not adversely affectthe reaction. The reaction temperature is not critical and the reactionis usually carried out under cooling, at ambient temperature or underwarming.

PREPARATION (4)

The compound (XI) can be prepared by reacting the compound (X) with anacid and/or acid anhydride such as acetic acid and/or acetic anhydride.The reaction of this process can preferably be carried out in thepresence of alkali metal perhaloate (e.g., sodium perchlorate, sodiumperiodate, potassium perchlorate, etc.), alkaline earth metalperchlorate (e.g., magnesium perchlorate, calcium perchlorate, etc.) andthe like, and an acid such as an organic acid (e.g., formic acid, aceticacid etc.) or an inorganic acid (e.g., hydrochloric acid).

The reaction temperature is not critical and the reaction is usuallycarried out under warming.

PREPARATIONS (5) and (7)

The preparation (5) and (7) can be carried out in a conventional manneras shown in Process 2 or 4.

In the preparation (5), according to reaction conditions, there may beobtained the product having R^(1a) or the product having amino groupinstead of R^(1a), and they are subsequently reacted with the compound(XII) or a salt thereof to give the compound (IIIa) or (IIIb),respectively, as shown in Preparation (6).

PREPARATION (6)

Suitable salt of the compound (XII) is a conventional acid salt such asan inorganic acid salt (e.g., hydrochloride, etc.) and an organic acidsalt (e.g., p-toluenesulfonic acid salt, etc). When salt of saidcompound (XII) is used in this process, the reaction is usually carriedout in the presence of a base such as an alkali metal hydroxide (e.g.,sodium hydroxide, potassium hydroxide, etc.). The reaction is usuallycarried out in a solvent such as water, an alcohol (e.g., methanol,ethanol, etc.) or any other solvent which does not adversely affect thereaction. The reaction temperature is not critical and the reaction isusually carried out at ambient temperature.

In the aforementioned reactions and/or in the post treatment of thereactions of the present invention, the aforementioned tautomericisomers may occasionally be transformed into the other tautomericisomers and such case is also included in the scope of the presentinvention.

In case that the object compound (I) is obtained in a form of the freeacid at 4 position and/or in case that the object compound (I) has freeamino group, it may be optionally transformed into its pharmaceuticallyacceptable salt as aforementioned by a conventional method.

The object compound (I) and pharmaceutically acceptable salt thereof ofthe present invention are all novel compounds which exhibit highantibacterial activity, inhibiting the growth of a wide variety ofpathogenic microorganisms including Gram-positive and Gram-negativebacteria and are useful as antibacterial agents.

Now, in order to show the utility of the object compound (I), withregard to some representative compounds of this invention, the test dataon the in vitro anti-bacterial activity are shown in the following.

TEST COMPOUNDS

(1)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer)

(2)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer)

(3)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(4)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(5)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(6)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(7)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(8)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(9)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer)

(10)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

TEST METHOD

In vitro antibacterial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁸ viable cells per ml.) was streaked on heartinfusion agar (HI-agar) containing graded concentrations of testcompounds, and minimal inhibitory concentration (MIC) was expressed interms of μg/ml. after incubation at 37° C. for 20 hours.

    __________________________________________________________________________    Test Results                                                                          MIC (μg/ml)                                                        Test    Test Compound                                                         Bacteria                                                                              (1)                                                                              (2)                                                                              (3)                                                                              (4)                                                                              (5)                                                                              (6)                                                                              (7)                                                                              (8)                                                                              (9)                                                                              (10)                                       __________________________________________________________________________    B. subtilis                                                                            3.13                                                                            3.13                                                                              6.25                                                                            3.13                                                                             6.25                                                                             3.13                                                                             1.56                                                                             3.13                                                                             12.5                                                                             6.25                                       ATCC 6633                                                                     E. coli NIHJ                                                                          0.2                                                                              0.05                                                                             0.2                                                                              0.2                                                                              0.1                                                                              0.1                                                                              0.78                                                                             0.1                                                                              0.05                                                                             0.1                                        JC-2                                                                          Kl. pneumoniae                                                                        0.2                                                                              0.1                                                                              0.1                                                                              0.39                                                                             0.05                                                                             0.39                                                                             3.13                                                                             0.39                                                                             0.2                                                                              0.2                                        12                                                                            Pr. vulgaris                                                                          0.2                                                                              0.2                                                                              0.1                                                                              0.2                                                                              0.05                                                                             0.2                                                                              0.39                                                                             0.39                                                                             0.05                                                                             0.78                                       Ps. aeruginosa                                                                         6.25                                                                            3.13                                                                              6.25                                                                            3.13                                                                             12.5                                                                             12.5                                                                             3.13                                                                             6.25                                                                             3.13                                                                             12.5                                       NCTC-10490                                                                    __________________________________________________________________________

For therapeutic administration, the object compound (I) of the presentinvention is used in the form of conventional pharmaceutical preparationwhich contains said compounds, as an active ingredient, in admixturewith a pharmaceutically acceptable carriers such as an organic orinorganic solid or liquid excipient which is suitable for oral,parenteral or external administration. The pharmaceutical preparationsmay be in solid form such as capsule, tablet, dragee, ointment orsuppository, or in liquid form such as solution, suspension, oremulsion. If needed, there may be included in the above preparationsauxiliary substances, stabilizing agents, wetting or emulsifying agents,buffers and the other commonly used additives.

While the dosage of the compounds may vary from and also depend upon theage, conditions of the patient, a kind of disease, a kind of thecompound (I) to be applied, etc., an average single dose of about 50mg., 100 mg., 250 mg, and 500 mg. of the object compound (I) of thepresent invention has proved to be effective in treating diseasesinfected by pathogenic bacteria.

In general, daily dose between 5 mg. and about 3,000 mg. or even moremay be administered to a patient.

The following preparations and examples are given for the purpose ofillustrating the present invention:

PREPARATION 1

Preparation of Methyl 5-amino-1,2,4-thiadiazole-3-carboxylate.

To a solution of 1-ethoxycarbonylformamidine. hydrobromide (16.6 g.) inabsolute methanol (84 ml) was added a solution of sodium (1.93 g) inabsolute methanol (42 ml) at 0° C. To the mixture were added alternatelybromine (12.8 g) and a solution of sodium (1.93 g) in absolute methanol(42 ml) at 0° C. and then to the suspension was added potassiumthiocyanate (8.1 g) in absolute methanol (100 ml). The reaction mixturewas stirred for an hour at 0° C. and for an additional 6 hours atambient temperature. The mixture was filtered through cellulose powderand the filtrate was evaporated to dryness. The residue was dissolved ina mixture of ethyl acetate and water, and then the ethyl acetate layerwas separated and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was triturated with diethyl ether to givethe title compound (9.0 g), mp. 202° to 205° C.

I.R. (Nujol): 3400, 3250, 3100, 1710, 1610, 1540 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 3.85 (3H, s), 8.25 (2H, s).

PREPARATION 2

Preparation of Methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate.

To a mixture of formic acid (33 g) and acetic anhydride (22 g) was addedmethyl 5-amino-1,2,4-thiadiazole-3-carboxylate (6.2 g), and then themixture was stirred for 2 days at ambient temperature. The reactionmixture was concentrated under reduced pressure and the residue wastriturated with a mixture of diethyl ether and n-hexane to give thetitle compound (7.2 g), mp. 210° to 215° C.

I.R. (Nujol): 3100, 1720, 1680 cm⁻¹.

N.M.R. (d₆ -DMSO) δ:3.90 (3H, s), 8.85 (1H, s).

PREPARATION 3

Preparation of5-Formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole.

To a mixture of methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate (9.2g) and methyl methylthiomethyl sulfoxide (6.1 g) inN,N-dimethylformamide (100 ml) was added 50% sodium hydride (7.1 g) withcooling in an ice-bath. The mixture was stirred for an hour at ambienttemperature and for an additional one hour at 40° C. After cooling toambient temperature, methylene chloride (300 ml) was added to thereaction mixture, and the resulting precipitates were collected byfiltration and washed with methylene chloride. The precipitates wereadded to a stirred mixture of hydrochloric acid (14.7 ml), ice-water(200 ml) and methylene chloride (200 ml). An insoluble material wasfiltered off and the methylene chloride layer was separated from thefiltrate. The solution was dried over anhydrous magnesium sulfate,evaporated and the residue was triturated with diethyl ether to give thetitle compound (4.5 g), mp. 130° to 132° C.

I.R. (Nujol): 3100, 1680, 1670 cm⁻¹.

    ______________________________________                                        N.M.R. (d.sub.6 -DMSO)                                                        δ:    2.22                                                                                               (3H, 2s)                                                 2.28                                                                          2.68                                                                                               (2H, 2s)                                                 2.85                                                                          5.70                                                                                               (1H, 2s)                                                 5.80                                                                          8.86                 (1H, s)                                      ______________________________________                                    

PREPARATION 4

Preparation of S-methyl(5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate.

A mixture of5-formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole(0.85 g) and sodium periodate (0.2 g) in glacial acetic acid (10 ml) wasstirred for 45 minutes at 70° C. The reaction mixture was evaporated andthe residue was dissolved in a mixture of ethyl acetate and water. Themixture was adjusted to pH 7 with an aqueous solution of sodiumbicarbonate and treated with an aqueous solution of sodium thiosulfate.The organic layer was separated, dried over anhydrous magnesium sulfateand evaporated to dryness. The residue was triturated with a mixture ofdiethyl ether and petroleum ether to give the title compound (280 mg),mp. 186° to 187° C.

I.R. (Nujol): 3100, 1680, 1660 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 2.55 (3H, s), 8.95 (1H, s).

PREPARATION 5

Preparation of2-Methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer).

A mixture of S-methyl (5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate(231 mg) in methanol (2 ml) and 1N-aqueous solution of potassiumhydroxide (3.5 ml) was stirred for an hour at ambient temperature. Themixture was adjusted to pH 7.6 with 1N hydrochloric acid, followed by anaddition of O-methylhydroxylamine hydrochloride (90 mg) and stirring for30 minutes at ambient temperature. The reaction mixture was neutralizedwith an aqueous solution of sodium bicarbonate and concentrated toremove methanol. The concentrated aqueous solution was adjusted to pH 4with hydrochloric acid and washed with ethyl acetate. The aqueous layerwas adjusted to pH 1 with hydrochloric acid, saturated with sodiumchloride and extracted with ethyl acetate. The extract was evaporated todryness and the residue was triturated with diethyl ether, collected byfiltration and then dried to give the title compound (80mg), mp. 185° to186° C.

I.R. (Nujol): 3150, 1720, 1690 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 3.98 (3H, s), 8.84 (1H, s).

PREPARATION 6

Preparation of2-Methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer)

A mixture of5-formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazol(3.2 g) and sodium periodate (0.8 g) in glacial acetic acid (32 ml) wasstirred for 45 minutes at 70° C. The resulting mixture was evaporatedand the residue was washed with n-hexane and then thereto were addedmethanol (20 ml) and 1N aqueous solution of potassium hydroxide (40 ml).The solution was stirred for an hour at ambient temperature. Thereaction mixture was adjusted to pH 8 with 1N hydrochloric acid,followed by an addition of O-methylhydroxylamine hydrochloride (0.96 g)and stirring for an hour at ambient temperature. The reaction mixturewas neutralized with an aqueous solution of sodium bicarbonate andconcentrated to remove methanol. The resulting aqueous solution waswashed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid,saturated with sodium chloride and extracted with with ethyl acetate.The extract was dried over anhydrous magnesium sulfate, evaporated, andthe residue was triturated with diisopropyl ether to give the titlecompound (1.02 g), mp. 185° to 186° C.

PREPARATION 7

Preparation of 2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer).

A solution of 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (1.4 g) in 1N aqueous solution of sodium hydroxide(19.1 ml) was heated at 50° to 55° C. for an hour. To the solution wasadded conc.hydrochloric acid (1.9 ml) under cooling in an ice-bath. Themixture was saturated with sodium chloride and extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate andevaporated to dryness. The residue was triturated with diethyl ether togive the title compound (0.9 g), mp. 180° to 182° C. (dec.).

I.R. (Nujol): 3450, 3250, 3100, 1715, 1610, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 3.90 (3H, s), 8.10 (3H, broad s).

PREPARATION 8

A mixture of5-formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole(10 g) and sodium periodate (2.0 g) in glacial acetic acid (50 ml) wasstirred for 50 minutes at 70° C. The solvent was evaporated and theresidue was washed with n-hexane. To the residue was added 1N aqueoussolution of sodium hydroxide (160 ml) and the mixture was stirred for anhour at ambient temperature. To the reaction mixture was addedO-ethylhydroxylamine hydrochloride (3.5 g) and the solution was adjustedto pH 3 to 4 with 10% hydrochloric acid and then stirred for an hour atambient temperature. After an insoluble material was filtered off, thefiltrate was washed with ethyl acetate, adjusted to pH 1 with 10%hydrochloric acid and extracted with ethyl acetate. The extract wasdried over magnesium sulfate and evaporated to dryness. The residue wastriturated with a mixture of diethyl ether and diisopropyl ether to give2-ethoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (4.5 g), mp 165° to 168° C. (dec.).

I.R. (Nujol): 3450, 3170, 3050, 1730, 1690, 1595, 1565 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 1.30 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz), 8.87(1H, s).

PREPARATION 9

The following compounds were obtained according to a similar manner tothat of Preparation 8.

(1) 2-Propoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 168° to 170° C. (dec.).

I.R. (Nujol): 3250, 3140, 1720, 1690, 1590, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 0.90 (3H, t, J=6 Hz), 1.4-1.9 (2H, m), 4.17 (2H, t,J=6 Hz), 8.85 (1H, s).

(2) 2-Isopropoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer), mp 180° to 182° C. (dec.).

I.R. (Nujol): 3230, 1720, 1690, 1590, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 1.25 (6H, d, J=6 Hz), 4.2-4.7 (1H, m), 8.85 (1H,s).

PREPARATION 10

A mixture of 2-ethoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (4.4 g) and 1N aqueous solution of sodium hydroxide(54 ml) was stirred for 2 hours at 50° to 55° C. The mixture was cooledin an ice bath, acidified with hydrochloric acid (5.4 ml) and extracredwith ethyl acetate. The extract was dried over magnesium sulfate andevaporated to dryness. The residue was triturated with diethyl ether togive 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (2.92 g), mp. 168° to 170° C. (dec.).

I.R. (Nujol): 3450, 3370, 3250, 3150, 1665, 1610, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 1.22 (3H, t, J=7 Hz), 4.17 (2H, q, J=7 Hz), 8.17(2H, broad s).

PREPARATION 11

The following compounds were obtained according to a similar manner tothat of Preparation 10.

(1) 2-Propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 100° to 103° C. (dec.).

I.R. (Nujol): 3620, 3520, 3350, 3120, 2600, 2500, 1720, 1620, 1550 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 1.00 (3H, t, J=6 Hz), 1.3-2.0 (2H, m), 4.13 (2H, t,J=6 Hz), 8.17 (2H, broad, s).

(2) 2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 152° to 155° C. (dec.).

I.R. (Nujol): 3450, 3300, 3200, 1730, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 1.22 (6H, d, J=6 Hz), 4.1-4.6 (1H, m), 8.20 (2H,broad s).

PREPARATION 12

A mixture of 7-aminocephalosporanic acid (14.31 g),5-allylthio-1,3,4-thiadiazole-2-thiol (14 g), sodium bicarbonate (10.6g), water (33 ml) and pH 6.4 phosphate buffer solution (105 ml) wasstirred for 4 hours at 65° to 70° C. To the reaction mixture was addedethyl acetate (50 ml) and the mixture was adjusted to pH 3 withhydrochloric acid. Precipitates were collected by filtration, washedwith water, methanol and acetone, and dried to give pale brown powder ofcrude7-amino-3-(5-allylthio-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (13.4 g). Said powder (10 g) was dissolved in a mixture of methanol(100 ml) and conc.hydrochloric acid (70 ml) and filtered. The filtratewas treated with an activated charcoal and adjusted to pH 3 with aqueousammonia. Ethyl acetate (50 ml) was added thereto and precipitates werecollected by filtration, washed with water and acetone, and dried togive pure object compound (5.2 g), mp 195° to 197° C.

I.R. (Nujol): 3150, 2700-2500, 1800, 1610, 1550-1510, 1040, 720 cm⁻¹.

PREPARATION 13

(1) A solution of methyl N-(3-methoxypropyl)-dithiocarbamate (100.2 g)in ethanol (300 ml) was added dropwise at 3° C. over 30 minutes to asolution of hydrazine hydrate (28 g) in ethanol (200 ml). The mixturewas stirred for 4.5 hours at 70° C. The reaction mixture wasconcentrated and to the residue were added water and diethyl ether. Thediethyl ether extract was dried over magnesium sulfate and evaporated invacuo to give pinkish oil of 4-(3-methoxypropyl)thiosemicarbazide (89.9g).

N.M.R. (CDCl₃) δ: 1.87 (2H, m), 3.33 (3H, s), 3.3-3.8 (4H, m), 4.0 (2H,broad s), 7.8 (1H, broad s).

(2) A mixture of 4-(3-methoxypropyl)thiosemicarbazide (89.9 g) andformic acid (450 ml) was refluxed with stirring for 8.5 hours at 105° C.Formic acid was removed in vacuo from the reaction mixture and to theresidue were added ethyl acetate (800 ml) and water (200 ml). Theseparated organic layer was washed with 5% aqueous solution of sodiumbicarbonate and with an aqueous solution of sodium chloride, dried overmagnesium sulfate and concentrated to give orange oil (77.52 g). To theoil were added a solution of sodium hydroxide (26 g) in water (260 ml)and methanol (40 ml), and then methanol was distilled off under reducedpressure. To the residue was added water (100 ml), and the mixture wasadjusted to pH 3 or 4 with 10% hydrochloric acid and extracted withethyl acetate (150 ml×2). The extracts were dried over magnesium sulfateand evaporated to give orange oil (40.32 g). The oil was purified bycolumn chromatography on silica gel (500 g) using ethyl acetate aseluent to give oil of 4-(3-methoxypropyl)-4H-1,2,4-triazole-3-thiol(8.95 g).

N.M.R. (CDCl₃) δ: 2.14 (2H, m), 3.40 (3H, s), 3.47 (2H, t, J=7 Hz), 4.18(2H, t, J=7 Hz), 7.94 (1H, s).

PREPARATION 14

(1) A solution of N-(3-aminopropyl)acetamide (146 g) in dioxane (710 ml)was added to a solution of 97% sodium hydroxide (52 g) in water (620 ml)and then carbon disulfide (96 g) was added dropwise thereto over 35minutes at -1° to 3° C. The mixture was stirred for 1 hour at 0° to 2°C. To the mixture containing sodium N-(3-acetamidopropyl)dithiocarbamatewas added dropwise methyl iodide (179 g) over 35 minutes at 0° to 5° C.and then the resulting mixture was stirred for 3 hours at the sametemperature. Dioxane was distilled off in vacuo from the reactionmixture and the residue was extracted with ethyl acetate (300 ml, 200ml×4). The extracts were dried over magnesium sulfate and concentratedin vacuo to give oil of methyl N-(3-acetamidopropyl)dithiocarbamate(193.18 g).

(2) A mixture of a solution of methylN-(3-acetamidopropyl)dithiocarbamate (193 g) in dioxane (610 ml) and asolution of sodium azide (79.42 g) in water (500 ml) was refluxed understirring for 4 hours. Dioxane was distilled off and the remainingaqueous layer was washed with diethyl ether (150 ml×2), adjusted to pH 1with 17.5% hydrochloric acid, and cooled in an ice bath. Precipitateswere collected by filtration and washed with ice-water to give whitepowder of 1-(3-acetamidopropyl)-1H-tetrazol-5-thiol (91.75 g), mp. 152°to 154° C.

N.M.R. (d₆ -DMSO) δ: 1.87 (3H, s), 1.97 (2H, m), 3.17 (2H, m), 4.28 (2H,t, J=7 Hz), 7.9 (1H, broad s), 15.0 (1H, broad s).

(3) A mixture of 1-(3-acetamidopropyl)-1H-tetrazole-5-thiol (85 g) and6N hydrochloric acid (1 l) was refluxed for 75 minutes under stirring.The reaction mixture was concentrated in vacuo and precipitates werecollected by filtration and washed with hexane and diethyl ether to give1-(3-aminopropyl)-1H-tetrazole-5-thiol hydrochloride (67.15 g).

N.M.R. (D₂ O) δ: 2.45 (2H, m), 3.23 (2H, t, J=7 Hz), 4.50 (2H, t, J=7Hz).

(4) A solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (12.3g) in dioxane (30 ml) was added under ice-cooling to a stirred solutionof 1-(3-aminopropyl)-1H-tetrazole-5-thiol hydrochloride (9.78 g) andtriethylamine (11.1 g) in a mixture of dioxane (25 ml) and water (25ml), and then the resulting mixture was stirred for 1.75 hours atambient temperature. Dioxane was distilled off and to the residue wereadded diethyl ether and a small amount of water. After shaking, theaqueous layer was separated and the organic layer was extracted twicewith 10% potassium carbonate. The extracts combined with the separatedaqueous layer were washed three times with diethyl ether, adjusted to pH1 with hydrochloric acid and extracted with diethyl ether. The extractwas washed with water, dried and evaporated in vacuo. The residual oil(10.92 g) was pulverized with diisopropyl ether to give1-[3-(N-t-butoxycarbonylamino)propyl]-1H-tetrazole-5-thiol (9.6 g), mp.75° to 77° C.

I.R. (Nujol): 3380, 3260, 1650, 1530, 1170, 1050 cm⁻¹.

N.M.R. (CDCl₃) δ: 1.50 (9H, s), 2.14 (2H, m), 3.25 (2H, m), 4.39 (2H, t,J=7 Hz), 4.9-6.7 (1H, broad).

PREPARATION 15

(1) To a mixture of methyl 5-amino-1,2,4-thiadiazole-3-carboxylate (26g), conc.hydrochloric acid (490 ml) and a small amount of copper wasadded dropwise over 40 minutes a solution of sodium nitrite (22.5 g) inwater (28 ml) at -10° to -15° C. The mixture was stirred for 1.5 hoursat the same temperature and for 30 minutes at 50° C. The reactionmixture was poured into ice-water (500 ml) and extracted with ethylacetate. The extract was washed, dried and concentrated to give whitepowder of methyl 5-chloro-1,2,4-thiadiazole-3-carboxylate (8.9 g).

I.R. (Nujol): 1730, 1430, 1385, 1320, 1220, 1065, 980, 830 cm⁻¹.

N.M.R. (CDCl₃) δ: 4.01 (3H, s).

(2) A mixture of methyl 5-chloro-1,2,4-thiadiazole-3-carboxylate (7.80g), thiourea (3.32 g), tetrahydrofuran (24 ml) and water (8 ml) wasgently boiled for 6.5 hours. The reaction mixture was post-treatedaccording to conventional manner to give yellow powder to methyl5-mercapto-1,2,4-thiadiazole-3-carboxylate (7.1 g), mp. 126° to 127° C.

I.R. (Nujol): 1730, 1430, 1360, 1270, 1060 cm⁻¹.

N.M.R. (d₆ -DMSO) δ: 3.91 (3H, s), 9.33 (1H, m).

PREPARATION 16

(1) Trichloromethylsulfur monochloride (88.33 g) was added at 0° C. to asolution of 2-allylisothiourea hydrobromide (93.6 g) in water (285 ml)and then a solution of sodium hydroxide (76 g) in water (300 ml) wasadded dropwise thereto over 4 hours with stirring. After stirring for 1hour, the reaction mixture was post-treated according to conventionalmanner to give reddish brown oil of3-allylthio-5-chloro-1,2,4-thiadiazole (84 g), bp. 105° to 111° C./13mmHg.

I.R. (Film): 1450, 1220, 1070 cm⁻¹.

N.M.R. (CDCl₃) δ: 3.90 (2H, d, J=6 Hz), 5.15-5.47 (2H, m), 5.67-6.34(1H, m).

(2) A mixture of 3-allylthio-5-chloro-1,2,4-thiadiazole (15.0 g),thiourea (5.95 g), tetrahydrofuran (45 ml) and water (15 ml) was gentlyboiled for 8.5 hours at 65° C. The reaction mixture was post-treatedaccording to conventional manner to give powder of3-allylthio-1,2,4-thiadiazole-5-thiol (8.5 g), mp. 107° to 108° C.

I.R. (Nujol): 1510, 1430, 1170, 1095, 900 cm⁻¹.

PREPARATION 17

(1) A solution of N-(2-aminopropyl)acetamide (82.9 g) in dioxane (415ml) was added to a solution of 97% sodium hydroxide (29.5 g) in water(330 ml). To the mixture was added dropwise at 0° to 5° C. over 25minutes carbon disulfide (54.5 g), after which the mixture was stirredfor 1 hour at 0° to 5° C. Methyl iodide (101.5 g) was added dropwiseover 30 minutes at 0° to 3° C. to the resultant mixture and the mixturewas stirred for 3 hours at the same temperature. The reaction mixturewas concentrated and extracted with ethyl acetate (200 ml, 100 ml×2).The extracts were dried over magnesium sulfate and evaporated to giveoil (164.2 g). The oil was subjected to column chromatography on silicagel (900 g) and successively eluted with a mixture of benzene and ethylacetate (1:1) and ethyl acetate to give oil of a mixture of methylN-(2-acetamidopropyl)dithiocarbamate and methylN-[1-(acetamidomethyl)ethyl]dithiocarbamate (114.1 g).

I.R. (Film): 3400-3200, 1730, 1670-1630, 1560-1500, 1310, 1280, 1250,1150, 960 cm⁻¹.

(2) A mixture of methyl N-(2-acetamidopropyl)dithiocarbamate and methylN-[1-(acetamidomethyl)ethyl]dithiocarbamate (100 g) in dioxane (300 ml)and a solution of sodium azide (41 g) in water (270 ml) were stirred for4.5 hours under reflux. The reaction mixture was concentrated to halfvolume under reduced pressure, washed with diethyl ether and acidifiedwith concentrated hydrochloric acid. The resulting precipitate wascollected by filtration and washed with diethyl ether to give paleyellow powder of 1-[1-(acetamidomethyl)ethyl]-1H-tetrazole-5-thiol(26.32 g), mp 176° to 178° C.

I.R. (Nujol): 3420, 2850, 1640, 1550, 1520, 1390, 1350, 1310, 1210,1050, 990 cm⁻¹.

N.M.R. (d₆ -DMSO,δ): 1.40 (3H, d, J=7 Hz), 1.75 (3H, s), 3.51 (2H, m),4.91 (1H, m), 8.00 (1H, t, J=6 Hz).

(3) A mixture of 1-[1-(acetamidomethyl)ethyl]-1H-tetrazole-5-thiol (23g) and 6N aqueous hydrochloric acid (300 ml) was refluxed for 2 hoursunder stirring and evaporated to dryness. The residue was trituratedwith diethyl ether to giver1-[1-(aminomethyl)ethyl]-1H-tetrazole-5-thiol hydrochloride (19 g), mp208° to 210° C.

I.R. (Nujol): 2800-2400, 1610, 1600, 1510, 1285, 1200, 1050 cm⁻¹.

N.M.R. (D₂ O,δ): 1.62 (3H, d, J=7 Hz), 3.70 (2H, m), 5.23 (1H, m).

(4) To a solution of 1-[1-(aminomethyl)ethyl]-1H-tetrazole-5-thiolhydrochloride (17 g) and triethylamine (19.33 g) in 50% aqueous dioxane(80 ml) was added a solution of2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (21.4 g) in dioxane (50ml) under cooling in an ice bath. The mixture was stirred for 1.5 hoursat ambient temperature and concentrated to third volume. The aqueoussolution was washed with diethyl ether and the washings were reextractedwith aqueous solution of potassium carbonate. The two aqueous solutionswere combined, washed with diethyl ether and mixed with ethyl acetate.The mixture was acidified with 10% hydrochloric acid and the organiclayer was separated out. The solution was dried over magnesium sulfateand evaporated to dryness. The residue was triturated with n-hexane togive 1-[1-{(N-t-butoxycarbonylamino)methyl}ethyl]-1H-tetrazole-5-thiol(19.15 g), mp 156° to 158° C.

I.R. (Nujol): 3270, 3070, 2850, 1660, 1530, 1500, 1390, 1340, 1300,1180, 1040 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.40 (9H, s), 1.52 (3H, d, J=7 Hz), 3.41 (2H, m),4.95 (1H, m), 7.05 (1H, m).

EXAMPLE 1

Preparation of7-[2-Methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

A mixture of N,N-dimethylformamide (6 ml) and phosphorus oxychloride(918 mg) was stirred for 30 minutes at ambient temperature. To themixture were added methylene chloride (6 ml) and2-methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (1.1 g) at -15° to -10° C., followed by stirring for 30 minutesat the same temperature. A mixture of7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (1.97 g) and trimethylsilylacetamide (6 g) in methylene chloride(60 ml) was warmed to make a clear solution. The solution was cooled to-15° C. and added to the above obtained solution. The reaction mixturewas stirred for an hour at 0° C. and poured into a cold aqueous solutionof sodium bicarbonate. The aqueous layer was separated, adjusted to pH 2with 10% hydrochloric acid and extracted with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate and evaporated to dryness.The residue was triturated with diethyl ether to give a crude product ofthe title compound (2.75 g). The crude material was dissolved in anaqueous solution of sodium bicarbonate and reprecipitated with dilutedhydrochloric acid to give the pure title compound (1.5 g), mp. 170° to175° C. (dec.).

I.R. (Nujol): 3300, 1780, 1680 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.90 (2H, broad s), 3.95 L (3H, s), 4.00 (3H, s),4.33 (2H, broad s), 5.17 (1H, d, J=4 Hz), 5.87 (1H, 2d, J=4, 8 Hz), 8.83(1H, s), 9.70 (1H, d, J=8 Hz).

EXAMPLE 2

Preparation of7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (100 mg) and phosphorus oxychloride (306 mg) in methylenechloride (5 ml) was stirred for 30 minutes at ambient temperature. Tothe mixture was added N,N-dimethylformamide (0.2 ml) under cooling in anice-bath, followed by stirring for 30 minutes. A mixture of7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (300 mg) and trimethylsilylacetamide (0.9 g) in methylene chloride(9 ml) was warmed to make a clear solution. The solution was cooled inan ice-bath and added to the above obtained solution, followed bystirring for 30 minutes at 0° C. The reaction mixture was poured into acold aqueous solution of sodium bicarbonate. The aqueous layer wasseparated, adjusted to pH 1 with 10% hydrochloric acid and extractedwith ethyl acetate. The extract was dried over anhydrous magnesiumsulfate and evaporated to dryness. The residue was triturated withdiethyl ether to give a crude product of the title compound (120 mg).The crude material was dissolved in an aqueous solution of sodiumbicarbonate and reprecipitated with diluted hydrochloric acid to givethe pure title compound (60 mg), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 1770, 1660, 1610, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.73 (2H, broad s), 3.97 (6H, s), 4.33 (2H, broads), 5.13 (1H, d, J=4 Hz), 5.83 (1H, 2d, J=4, 8.5 Hz), 8.12 (2H, s), 9.57(1H, d, J=8.5 Hz).

EXAMPLE 3

Preparation of7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer).

A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (1.21 g) and phosphorus oxychloride (3.67 g) in methylenechloride (30 ml) was stirred for an hour at ambient temperature, cooledand thereto was added N,N-dimethylformamide (2.4 ml), followed bystirring for an additional 30 minutes under ice-cooling. A mixture of7-aminocephalosporanic acid (2.94 g) and trimethylsilylacetamide (10 g)in methylene chloride (50 ml) was warmed to make a clear solution. Thesolution was cooled in an ice-bath and added to the above obtainedsolution, followed by stirring for 30 minutes at 0° to 5° C. Thereaction mixture was poured into a mixture of a saturated aqueoussolution of sodium bicarbonate (60 ml) and ice. The aqueous layer (200ml., pH 7 to 8) was separated and thereto was added ethyl acetate. Theresulting mixture was adjusted to pH 1 with 10% hydrochloric acid,saturated with sodium chloride and filtered to remove an insolublematerial. The ethyl acetate layer was separated, dried over magnesiumsulfate and evaporated. The residue was triturated with diethyl ether togive a crude product of the title compound (2.4 g). The crude materialwas dissolved in an aqueous solution of sodium bicarbonate, treated withactivated charcoal (100 mg), adjusted to pH 2 with 10% hydrochloricacid. The precipitates were collected by filtration, washed withice-water and dried to give the title compound (1.2 g), mp. 180° to 185°C. (dec.).

I.R. (Nujol): 3350, 1780, 1730, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.97 (3H, s), 3.50 (2H, s), 3.87 (3H, s),##STR12## 5.08 (1H, d, J=4 Hz), 5.77 (1H, 2d, J=4, 8.5 Hz), 8.06 (2H,s), 9.50 (1H, d, J=8.5 Hz).

EXAMPLE 4

Preparation of7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (1.01 g) and phosphorus oxychloride (3.06 g) in methylenechloride (25 ml) was stirred for 2 hours at ambient temperature, cooledto 0° C. and thereto was added N,N-dimethylformamide (2.0 ml), followedby stirring for an additional 45 minutes at 0° C. A mixture of7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (4.9 g) andtrimethylsilylacetamide (11 g) in methylene chloride (100 ml) was warmedto make a clear solution. The solution was cooled to -15° C. and addedto the above obtained solution, followed by stirring for 30 minutes at0° C. The reaction mixture was poured into a cold aqueous solution ofsodium bicarbonate. The aqueous layer was separated and thereto wasadded ethyl acetate. The resulting mixture was adjusted to pH 2 with 10%hydrochloric acid, filtered to remove an insoluble material and thensaturated with sodium chloride. The ethyl acetate layer was separated,dried over magnesium sulfate and evaporated. The residue was trituratedwith diethyl ether to give a crude product of the title compound (1.2g). The crude material was dissolved in an aqueous solution of sodiumbicarbonate, and reprecipitated with 10% hydrochloric acid. Theprecipitates were collected by filtration, washed with water and driedto give the title compound (0.35 g), mp. 185° to 190° C. (dec.).

I.R. (Nujol): 3350, 1780, 1720, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.52 (2H, s), 3.92 (3H, s), ##STR13## 5.14 (1H, d,J=4 Hz), 5.80 (1H, 2d, J=4,8 Hz), 6.58 (2H, s), 8.10 (2H, s), 9.54 (1H,d, J=8 Hz).

EXAMPLE 5

Preparation of7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (1.21 g) and phosphorus oxychloride (3.67 g) in methylenechloride (30 ml) was stirred for two hours at ambient temperature,cooled to 0° C. and thereto was added N,N-dimethylformamide (2.4 ml),followed by stirring for an additional 45 minutes at 0° C. A mixture of7-amino-2-methyl-3-cephem-4-carboxylic acid (3.0 g) andtrimethylsilylacetamide (10 g) in methylene chloride (50 ml) was warmedto make a clear solution. The solution was cooled to -15° C. and addedto the above obtained solution, followed by stirring for 30 minutes at0° C. The reaction mixture was poured into a cold aqueous solution ofsodium bicarbonate. The aqueous layer was separated and thereto wasadded ethyl acetate. The resulting mixture was adjusted to pH 2 with 10%hydrochloric acid and the ethyl acetate layer was separated, dried overanhydrous magnesium sulfate and then evaporated. The residue wastriturated with diethyl ether to give a crude product of the titlecompound (2.2 g). The crude material was dissolved in an aqueoussolution of sodium bicarbonate, adjusted to pH 2 with 10% hydrochloricacid. The precipitates were collected by filtration, washed withice-water and dried to give the title compound (1.6 g), mp. 175° to 180°C. (dec.).

I.R. (Nujol): 3350, 1775, 1675, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.43 (3H, d, J=6 Hz), 3.6-3.9 (1H, m), 3.93 (3H,s), 5.07 (1H, d, J=4 Hz), 5.87 (1H, 2d, J=4,8 Hz), 6.53 (1H, d, J=5 Hz),8.08 (2H, s), 9.55 (1H, d, J=8 Hz).

EXAMPLE 6

Preparation of 4-Nitrobenzyl7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer) (I) and 4-nitrobenzyl7-[2-methoxyimino-2-{5-{N'-(N,N-dimethylaminomethylene)amino}-1,2,4-thiadiazol-3-yl}acetamido]-3-cephem-4-carboxylate(syn isomer) (II).

A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (1.21 g) and phosphorus oxychloride (3.67 g) in methylenechloride (30 ml) was stirred for 2 hours at ambient temperature, cooledto 0° C. and thereto was added N,N-dimethylformamide (2.4 ml), followedby stirring for an additional 45 minutes at 0° C. A mixture of4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (2.68 g) andtrimethylsilylacetamide (8 g) in methylene chloride (80 ml) was stirredfor 2 hours at ambient temperature to make a clear solution. Thesolution was cooled to 0° C. and added to the above obtained solution,followed by stirring for 30 minutes at 0° to 5° C. The reaction mixturewas poured into a cold aqueous solution of sodium bicarbonate. Themethylene chloride layer was separated, dried over magnesium sulfate andevaporated. The residue was triturated with diethyl ether to give amixture of crude product of the title compound (I) and (II) (3.7 g). Thecrude powder was subjected to column chromatography on silica gel usingethyl acetate as an eluent to firstly give the title compound (I) (1.0g), mp. 150° to 155° C. From subsequent fractions, there was obtainedthe title compound (II) (1.1 g), mp. 115° to 120° C. The title compound(I) has the following I.R. and N.M.R. spectra;

I.R. (Nujol): 3300, 1770, 1720, 1670, 1620, 1510 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.63 (2H, broad d, J=3 Hz), 3.93 (3H, s), 5.17(1H, d, J=4 Hz), 5.43 (2H, s), 5.92 (1H, 2d, J=4,9 Hz), 6.67 (1H, t, J=3Hz), 7.70 (2H, d, J=8 Hz), 8.08 (2H, s), 8.23 (2H, d, J=8 Hz), 9.55 (1H,d, J=9 Hz).

The title compound (II) has the following I.R. and N.M.R. spectra;

I.R. (Nujol): 3300, 1770, 1720, 1670, 1610 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.07 (3H, s), 3.20 (3H, s), 3.63 (2H, broad d, J=3Hz), 3.97 (3H, s), 5.17 (1H, d, J=4 Hz), 5.43 (2H, s), 5.93 (1H, 2d,J=4,8 Hz), 6.67 (1H, t, J=3 Hz), 7.70 (2H, d, J=8 Hz), 8.23 (2H, d, J=8Hz), 8.47 (1H, s), 9.60 (1H, d, J=8 Hz).

EXAMPLE 7

A mixture of 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (1.3 g) and phosphorus oxychloride (3.67 g) in methylenechloride (30 ml) was stirred for 2 hours at ambient temperature and thencooled to -12° to -15° C. To the cold mixture was addeddimethylformamide (2.4 ml) and the mixture was stirred for 45 minutes at-8° to -10° C. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(2.9 g) and trimethylsilylacetamide (8 g) in methylene chloride (40 ml)was warmed to make a solution. The solution was cooled to -25° C. andadded to the above activated mixture. The reaction mixture was stirredfor 30 minutes at -8° to -10° C. and poured into a cold aqueous solutionof sodium bicarbonate. The mixture was stirred for 30 minutes at ambienttemperature and the aqueous layer was separated out. The aqueoussolution was adjusted to pH 1 with 10% hydrochloric acid and extractedwith ethyl acetate. The extract was dried over magnesium sulfate andevaporated to dryness. The residue was triturated with diethyl ether togive a crude7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.6 g). The crude product was dissolved in an aqueoussolution of sodium bicarbonate and reprecipitated with an addition of10% hydrochloric acid to give pure object compound (1.92 g). mp 150° to155° C. (dec.)

I.R. (Nujol): 3350, 3230, 1775, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (3H, t, J=7 Hz), 3.72 (2H, broad s), 4.22(2H, q, J=7 Hz) 4.32 and 4.55 (2H, ABq, J=13 Hz), 5.17 (1H,d, J=5 Hz),5.83 (1H, dd, J=5 and 8 Hz), 8.13 (2H, broad s), 9.56 (1H, d, J=8 Hz),9.57 (1H, s).

EXAMPLE 8

A mixture of 2-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (1.38 g) and phosphorus oxychloride (3.67 g) inmethylene chloride (30 ml) was stirred for 1.5 hours at ambienttemperature and then cooled to -12° to -15° C. To the cold mixture wasadded dimethylformamide (2.4 ml) and the mixture was stirred for 45minutes at -8° to -10° C. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(2.9 g) and trimethylsilylacetamide (8 g) in methylene chloride (40 ml)was warmed to make a solution. The solution was cooled to -25° C. andadded to the above activated mixture. The reaction mixture was stirredfor 30 minutes at -10° C. and poured into a cold aqueous solution ofsodium bicarbonate. The mixture was stirred for 30 minutes at ambienttemperature and the aqueous layer was separated out. The aqueoussolution was adjusted to pH 1 with 10% hydrochloric acid and extractedwith ethyl acetate. The extract was dried over magnesium sulfate andevaporated to dryness. The residue was triturated with diethyl ether togive a crude7-[2-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.25 g). The crude product was dissolved in a mixtureof acetone and ethyl acetate. The acetone was evaporated and theprecipitates were collected by filtration to give the same objectcompound (1.53 g), which was dissolved in an aqueous solution of sodiumbicarbonate and reprecipitated with an addition of 10% hydrochloric acidto give pure object compound (1.23 g). mp 145° to 150° C. (dec.)

I.R. (Nujol): 3370, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.25 (6H, d, J=6 Hz), 3.68 (2H, broad s), 4.2-4.6(1H, m), 4.28 and 4.55 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=5 Hz), 5.80(1H, dd, J=5 and 8 Hz) 8.12 (2H, broad s), 9.50 (1H, d, J=8 Hz), 9.53(1H, s).

EXAMPLE 9

A mixture of phosphorus pentachloride (250 mg) and methylene chloride (5ml) was stirred for 10 minutes at ambient temperature.2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (230 mg) was added thereto at -15° C. and the mixture wasstirred for 45 minutes at -10° to -13° C. A solution of7-aminocephalosporanic acid (350 mg) and trimethylsilylacetamide (1 g)in methylene chloride (5 ml) was added thereto at -15° C. and themixture was stirred for 30 minutes at -10° C. To the reaction mixturewere added a saturated aqueous solution of sodium bicarbonate (8 ml) andwater (10 ml), and then methylene chloride was evaporated. To theaqueous layer was added ethyl acetate, and the mixture was adjusted topH 2 with 10% hydrochloric acid and then extracted with ethyl acetate.The extract was dried over magnesium sulfate and concentrated. Theresidue was triturated with diethyl ether and precipitates werecollected by filtration to give7-[2-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (450 mg). mp 150° to 155° C. (dec.)

I.R. (Nujol): 3300, 1780, 1725, 1660, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.30 (6H, d, J=6 Hz), 2.08 (3H, s), 3.62 (2H,broad s), 4.33-4.67 (1H, m), 4.77 and 5.03 (2H, ABq, J=13 Hz), 5.22 (1H,d, J=4 Hz), 5.87 (1H, dd, J=4 and 8 Hz), 8.17 (2H, s), 9.53 (1H, d, J=8Hz).

EXAMPLE 10

To a cold solution of phosphorus pentachloride (2.5 g) in methylenechloride (60 ml) was added2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(2.16 g) at -15° C. and the mixture was stirred for 30 minutes at thesame temperature. On the other hand, a mixture of 4-nitrobenzyl7-amino-3-cephem-4-carboxylate (4.0 g) and trimethylsilylacetamide (12g) in methylene chloride (60 ml) was warmed to make a clear solution andthen cooled to -10° C. The solution was added to the above activatedmixture and the mixture was stirred for 0.5 hour at 0° to 5° C. Thereaction mixture was poured into cold aqueous solution (150 ml) ofsodium bicarbonate (7.0 g). The organic layer was dried over magnesiumsulfate and evaporated to dryness. The residue was pulverized withdiethyl ether and precipitates were collected by filtration and dried togive 4-nitrobenzyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate (synisomer) (5.5 g), mp. 120° to 125° C. (dec.).

I.R. (Nujol): 3300, 1770, 1720, 1670, 1620, 1605, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.23 (3H, t, J=7 Hz), 3.50-3.70 (2H, m), 4.33 (2H,q, J=7 Hz), 5.10 (1H, d, J=4 Hz), 5.37 (2H, s), 5.88 (1H, dd, J=4 and 8Hz), 6.60 (1H, t, J=4 Hz), 7.63 (2H, d, J=8 Hz), 8.07 (2H, s), 8.17 (2H,d, J=8 Hz), 9.50 (1H, d, J=8 Hz).

EXAMPLE 11

The following compounds were prepared by similar manners to thosedescribed in Examples 1 to 10.

(1)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3350, 1780, 1680, 1625, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.72 (3H, s), 3.70 (2H, s), 4.00 (3H, s), 4.25,4.53 (2H, ABq, J=14 Hz), 5.16 (1H, d, J=4 Hz), 5.83 (1H, 2d, J=4,8 Hz),8.13 (2H, s), 9.58 (1H, d, J=8 Hz).

(2)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,5-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 172° to 177° C. (dec.).

I.R. (Nujol): 3350, 1775, 1680, 1625, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.80 (2H, s), 4.00 (3H, s), 4.38, 4.67 (2H, ABq,J=14 Hz), 5.22 (1H, d, J=5 Hz), 5.90 (1H, 2d, J=5,8 Hz), 8.20 (2H, s),9.63 (1H, s), 9.67 (1H, d, J=8 Hz).

(3)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 172° C. (dec.).

I.R. (Nujol): 3350, 1780, 1680, 1625, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.67 (2H, s), 3.93 (3H, s), ##STR14## 4.9-5.5 (5H,m), 5.6-6.3 (2H, m), 8.10 (2H, s), 9.53 (1H, d, J=8 Hz).

(4)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3350, 1775, 1680, 1630, 1530 cm⁻¹.

(5)7-[2-Propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 130° to 133° C. (dec.)

I.R. (Nujol): 3380, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 0.92 (3H, t, J=6 Hz), 1.3-2.1 (2H, m), 3.12 (2H,t, J=6 Hz), 3.72 (2H, broad s), 4.33 and 4.58 (2H, ABq, J=13 Hz), 5.17(1H, d, J=5 Hz), 5.82 (1H, dd, J=5 and 8 Hz), 8.12 (2H, broad s), 9.53(1H, d, J=8 Hz), 9.57 (1H, s).

(6)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(N-t-butoxycarbonylamino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1670 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.40 (9H, s), 3.70 (2H, broad s), 3.93 (3H, s),4.30 and 4.53 (2H, ABq, J=13 Hz), 4.53 (2H, d, J=5 Hz), 5.17 (1H, d, J=4Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.13 (2H, s), 9.57 (1H, d, J=8 Hz).

(7)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-allylthio-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 3.9-4.0 (2H, m), 3.93 (3H, s),4.27 and 4.50 (2H, ABq, J=14 Hz), 5.15 (1H, d, J=4 Hz), 5.1-5.5 (2H, m),5.6-6.2 (1H, m), 5.83 (1H, dd, J=4 and 8 Hz), 8.13 (2H, s), 9.57 (1H, d,J=8 Hz).

(8)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetylthiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 178° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.83 (3H, s), 3.27 and 3.57 (2H, ABq, J=18 Hz),3.83 (3H, s), 3.73 and 3.97 (2H, ABq, J=13 Hz), 5.04 (1H, d, J=4 Hz),5.72 (1H, d, J=4 Hz), 5.72 (1H, dd, J=4 and 8 Hz), 8.07 (2H, s), 9.47(1H, d, J=8 Hz).

(9)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-pyrazinylthiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 174° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(10)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-thiazolin-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(11)7-[2-Methoxymino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3400, 3250, 1885, 1725, 1670, 1640, 1540 cm⁻¹.

(12)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)-ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 200° to 205° C. (dec.)

I.R. (Nujol): 3300, 1780, 1700, 1680, 1620, 1520 cm⁻¹.

(13)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-propyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(14)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-methoxypropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 167° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(15)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 178° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(16)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methoxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 174° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(17)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methylthiomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 173° to 175° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(18)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-propyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 182° to 184° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(19)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methylthiomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 178° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(20)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-isopropyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(21)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm⁻¹.

(22)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(2-hydroxyethyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(23)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-propyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 177° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(24)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 170° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(25)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methanesulfonamidomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(26)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-allylthio-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 173° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(27)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-mesylmethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(28) Sodium7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-sulfonatomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 205° to 210° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1530 cm⁻¹.

(29)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(30)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 185° to 190° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(31)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(3-methoxypropyl)-4H-1,2,4-triazol-3-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(32)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(2-aminoethyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 205° to 210° C. (dec.)

I.R. (Nujol): 3200, 1770, 1670, 1620, 1530 cm⁻¹.

(33)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 210° to 215° C. (dec.)

I.R. (Nujol): 3350, 3200, 1770, 1680, 1620 cm⁻¹.

(34)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 200° to 205° C. (dec.)

I.R. (Nujol): 3350, 3200, 1775, 1670, 1620, 1530 cm⁻¹.

(35)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer). mp 140° to 156° C. (dec.)

I.R. (Nujol): 3370, 3250, 1780, 1730, 1680, 1620, 1530, 1380, 1240, 1040cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.23 (3H, t, J=7 Hz), 2.00 (3H, s), 3.7 (2H, m),4.17 (2H, q, J=7 Hz), 4.63 and 5.00 (2H, ABq, J=12 Hz), 5.10 (1H, d,J=4.5 Hz), 5.80 (1H, dd, J=4.5 and 8.0 Hz), 8.1 (2H, broad s), 9.53 (1H,d, J=8 Hz).

(36)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 183° to 188° C. (dec.)

I.R. (Nujol): 3370, 3240, 1780, 1690, 1630, 1530, 1380, 1260, 1170, 1040cm⁻¹.

(37)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3360, 3240, 1780, 1690, 1630, 1530, 1375, 1250, 1170, 1040cm⁻¹.

(38)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 156° to 159° C. (dec.)

I.R. (Nujol): 3360, 3250, 1780, 1680, 1625, 1380, 1080, 1040 cm⁻¹.

(39)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 177° to 180° C. (dec.)

I.R. (Nujol): 3380, 3250, 1775, 1670, 1620, 1535, 1380, 1040 cm⁻¹.

(40)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.).

I.R. (Nujol): 3380, 3250, 1780, 1680, 1630, 1530, 1380, 1040 cm⁻¹.

(41)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3240, 1780, 1680, 1620, 1530, 1380, 1040 cm⁻¹.

(42)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 198° to 205° C. (dec.)

I.R. (Nujol): 3350, 3250, 1775, 1680, 1620, 1535, 1380, 1040 cm⁻¹.

(43)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 173° C. (dec.)

I.R. (Nujol): 3350, 3240, 1780, 1675, 1625, 1530, 1380, 1040, 720 cm⁻¹.

(44)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 185° to 190° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm⁻¹.

(45)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methoxycarbonyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1740, 1680, 1620, 1530 cm⁻¹.

(46)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-carboxy-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1730, 1680, 1620, 1530 cm⁻¹.

(47)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 182° to 185° C. (dec.).

I.R. (Nujol): 3350, 3200, 1770, 1670, 1620, 1530, 1380, 1040 cm⁻¹.

(48)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 195° to 210° C. (dec.).

I.R. (Nujol): 3340, 3210, 1770, 1675, 1620, 1530, 1380, 1040 cm⁻¹.

(49) 4-Nitrobenzyl7-[2-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp. 145° to 150° C. (dec.).

I.R. (Nujol): 3300, 1775, 1720, 1670, 1620, 1600, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (6H, d, J=7 Hz), 3.53-3.77 (2H, m), 4.17-4.67(1H, m), 5.17 (1H, d, J=4 Hz), 5.42 (2H, s), 5.93 (1H, dd, J=4 and 8Hz), 6.67 (1H, t, J=4 Hz), 7.86 (2H, d, J=8 Hz), 8.13 (2H, s), 8.23 (2H,d, J=8 Hz), 9.53 (1H, d, J=8 Hz).

(50)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(N-t-butoxycarbonylamino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 1780, 1670, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.18 (6H, d, J=6 Hz), 1.32 (9H, s), 3.62 (2H,broad s), 4.17-4.73 (5H, m), 5.17 (1H, d, J=4 Hz), 5.84 (1H, dd, J=4 and8 Hz), 8.18 (2H, s), 9.63 (1H, d, J=8 Hz).

(51)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 cm⁻¹.

(52)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-carboxymethylthio-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1720, 1680, 1620, 1530 cm⁻¹.

(53)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(54)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 142° to 147° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1690, 1630, 1530 cm⁻¹.

(55)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1710, 1670, 1625, 1525 cm⁻¹.

(56)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 135° to 140° C. (dec.).

I.R. (Nujol): 3350, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

(57)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹.

(58)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-carboxymethyl-3-oxo-2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 205° to 210° C. (dec.).

I.R. (Nujol): 3300, 1765, 1710, 1680, 1620, 1550, 1520 cm⁻¹.

(59)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methylamino-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3450, 3370, 3250, 1775, 1710, 1680, 1630, 1560 cm⁻¹.

(60)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-amino-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3350, 3210, 1770, 1670, 1620, 1520 cm⁻¹.

(61)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3370, 3250, 1785, 1690, 1630, 1530 cm⁻¹.

(62)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(acetamido)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3230, 1780, 1660, 1620, 1530 cm⁻¹.

(63)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(acetamidomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 160° to 165° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1660, 1620, 1530 cm⁻¹.

(64)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(N-t-butoxycarbonylaminomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° to 185° C. (dec.).

I.R. (Nujol): 3370, 3230, 1780, 1690, 1630, 1530 cm⁻¹.

(65)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N,N-dimethylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3350, 3200, 1770, 1670, 1610, 1530 cm⁻¹.

(66)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3150, 1770, 1720, 1670, 1620, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.93 (2H, t, J=9 Hz), 3.70 (2H, broad s), 3.92(3H, s), 4.27 and 4.43 (2H, ABq, J=14 Hz), 4.45 (2H, t, J=9 Hz), 5.17(1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.18 (2H, s), 9.67 (1H, d,J=8 Hz).

(67)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 123° to 125° C. (dec.).

I.R. (Nujol): 3300, 3200, 1750, 1720, 1680, 1620, 1520 cm⁻¹.

(68)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 210° to 215° C. (dec.).

I.R. (Nujol): 3350, 3200, 1750, 1670, 1620, 1530 cm⁻¹.

(69)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 195° to 200° C. (dec.).

I.R. (Nujol): 3350, 3250, 1775, 1680, 1620, 1530 cm⁻¹.

(70)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 185° to 190° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1610, 1530 cm⁻¹.

(71)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(aminomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3350, 3230, 1770, 1670, 1620, 1530 cm⁻¹.

(72)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp. 208° to 213° C. (dec.).

I.R. (Nujol): 3400, 3350, 3250, 1770, 1660, 1630, 1610, 1520 cm⁻¹.

(73)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1770, 1670, 1630, 1520 cm⁻¹.

EXAMPLE 12

To a cold solution of phosphorus pentachloride (3.12 g) in methylenechloride (37 ml) was added2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(1.01 g) at -15° C. and the mixture was stirred for 25 minutes at -10°to -13° C. and for 30 minutes at 0° to -3° C. On the other hand, amixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(1.82 g) and trimethylsilylacetamide (5 g) in methylene chloride (25 ml)was warmed to make a clear solution and then cooled to -10° C. Thesolution was added to the above activated mixture and the mixture wasstirred for 0.5 hour at -5° to 0° C. The reaction mixture was filteredand to the filtrate was added an aqueous solution of sodium bicarbonate(80 ml). The mixture was stirred at ambient temperature and methylenechloride was distilled off. The aqueous layer was adjusted to pH 1 with10% hydrochloric acid and subjected to column chromatography on DiaionHP-20 resin (200 ml) (Trademark: prepared by Mitsubishi ChemicalIndustries Ltd.) using successively water, 20% aqueous methanol (500 ml)and 40% aqueous methanol (500 ml) and the eluate was lyophilized to give7-[2-methoxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (synisomer) (440 mg), mp. 140° to 145° C. (dec.).

I.R. (Nujol): 3180, 1765, 1670, 1515 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.72 (2H, broad s), 3.93 (3H, s), 4.32 and 4.57(2H, ABq, J=13 Hz), 5.17 (1H, d, J=5 Hz), 5.85 (1H, dd, J=5 and 8 Hz),9.58 (1H, s), 9.63 (1H, d, J=8 Hz).

EXAMPLE 13

Preparation of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer).

In a mixture of tetrahydrofuran (20 ml), methanol (10 ml), acetic acid(0.25 ml) and water (2.5 ml) was dissolved 4-nitrobenzyl7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer) (0.87 g) and thereto was added 5% palladium-carbon (0.87g). The resulting mixture was shaken under a hydrogen atmosphere atatmospheric pressure and ambient temperature for 6 hours. The reactionmixture was filtered and the filtrate was evaporated to dryness. Theresidue was dissolved in an aqueous solution of sodium bicarbonate andthe solution was washed with ethyl acetate. The aqueous layer wasadjusted to pH 2 with 10% hydrochloric acid and extracted with ethylacetate. The extract was dried over magnesium sulfate and evaporated todryness. The residue was triturated with diethyl ether to give the titlecompound (350 mg), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3350, 1775, 1680, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.60 (2H, broad s), 3.93 (3H, s), 5.10 (1H, d, J=4Hz), 5.85 (1H, 2d, J=4,8 Hz), 6.50 (1H, t, J=4 Hz), 8.10 (2H, s), 9.57(1H, d, J=8 Hz).

EXAMPLE 14

A mixture of 4-nitrobenzyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer) (5.0 g) and 10% palladium on carbon (2.5 g) in 70% aqueoustetrahydrofuran (75 ml) was stirred under hydrogen atmosphere for 3hours at ambient temperature. The catalyst was removed by filtration andthe filtrate was concentrated to third volume. The residue was extractedwith ethyl acetate and transferred into an aqueous solution of sodiumbicarbonate. The aqueous layer was acidified to pH 3 with 10%hydrochloric acid and extracted with ethyl acetate. The extract wasdried over magnesium sulfate and concentrated to 10 ml under reducedpressure. The resultant precipitates were collected, washed with ethylacetate and dried to give7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer) (1.33 g), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1770, 1670, 1630, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.23 (3H, t, J=7 Hz), 3.58 (2H, broad s), 4.17(2H, q, J=7 Hz), 5.07 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 6.45(1H, t, J=4 Hz), 8.05 (2H, s), 9.50 (1H, d, J=8 Hz).

EXAMPLE 15

The following compounds were obtained according to similar manners tothose of Examples 13 and 14.

(1)7-[2-Methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 1780, 1680 cm⁻¹.

(2)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 1770, 1660, 1610, 1520 cm⁻¹.

(3)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp. 180° to 185° C. (dec.).

I.R. (Nujol): 3350, 1780, 1730, 1680, 1620, 1530 cm⁻¹.

(4)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 185° to 190° C. (dec.).

I.R. (Nujol): 3350, 1780, 1720, 1680, 1620, 1530 cm⁻¹.

(5)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3350, 1775, 1675, 1630, 1530 cm⁻¹.

(6)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3350, 1780, 1680, 1625, 1530 cm⁻¹.

(7)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 172° to 177° C. (dec.).

I.R. (Nujol): 3350, 1775, 1680, 1625, 1530 cm⁻¹.

(8)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 172° C. (dec.).

I.R. (Nujol): 3350, 1780, 1680, 1625, 1530 cm⁻¹.

(9)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp. 208° to 213° C. (dec.).

I.R. (Nujol): 3400, 3350, 3250, 1770, 1660, 1630, 1610, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (6H, d, J=6 Hz), 3.57 (2H, d, J=4 Hz),4.17-4.60 (1H, m), 5.07 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz),6.43 (1H, t, J=4 Hz), 8.07 (2H, s), 9.45 (1H, d, J=8 Hz).

(10)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(N-t-butoxycarbonylamino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 1780, 1670, 1620, 1530 cm⁻¹.

(11)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 cm⁻¹.

(12)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-carboxymethylthio-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1720, 1680, 1620, 1530 cm⁻¹.

(13)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(14)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 142° to 147° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1690, 1630, 1530 cm⁻¹.

(15)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1710, 1670, 1625, 1525 cm⁻¹.

(16)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 135° to 140° C. (dec.).

I.R. (Nujol): 3350, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

(17)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹.

(18)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-carboxymethyl-3-oxo-2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 205° to 210° C. (dec.).

I.R. (Nujol): 3300, 1765, 1710, 1680, 1620, 1550, 1520 cm⁻¹.

(19)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methylamino-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3450, 3370, 3250, 1775, 1710, 1680, 1630, 1560 cm⁻¹.

(20)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-amino-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3350, 3210, 1770, 1670, 1620, 1520 cm⁻¹.

(21)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3370, 3250, 1785, 1690, 1630, 1530 cm⁻¹.

(22)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(acetamido)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3230, 1780, 1660, 1620, 1530 cm⁻¹.

(23)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(acetamidomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 160° to 165° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1660, 1620, 1530 cm⁻¹.

(24)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(N-t-butoxycarbonylaminomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° to 185° C. (dec.).

I.R. (Nujol): 3370, 3230, 1780, 1690, 1630, 1530 cm⁻¹.

(25)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N,N-dimethylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3350, 3200, 1770, 1670, 1610, 1530 cm⁻¹.

(26)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3150, 1770, 1720, 1670, 1620, 1520 cm⁻¹.

(27)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 123° to 125° C. (dec.).

I.R. (Nujol): 3300, 3200, 1750, 1720, 1680, 1620, 1520 cm⁻¹.

(28)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 210° to 215° C. (dec.).

I.R. (Nujol): 3350, 3200, 1750, 1670, 1620, 1530 cm⁻¹.

(29)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 195° to 200° C. (dec.).

I.R. (Nujol): 3350, 3250, 1775, 1680, 1620, 1530 cm⁻¹.

(30)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 185° to 190° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1610, 1530 cm⁻¹.

(31)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(aminomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3350, 3230, 1770, 1670, 1620, 1530 cm⁻¹.

(32)7-[2-Methoxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 140° to 145° C. (dec.).

I.R. (Nujol): 3180, 1765, 1670, 1515 cm⁻¹.

(33)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3230, 1775, 1680, 1620, 1530 cm⁻¹.

(34)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3370, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

(35)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 150° to 155° C. (dec.)

I.R. (Nujol): 3300, 1780, 1725, 1660, 1520 cm⁻¹.

(36)7-[2-Propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 130° to 133° C. (dec.)

I.R. (Nujol): 3380, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

(37)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(N-t-butoxycarbonylamino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1670 cm⁻¹.

(38)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-allylthio-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620 cm⁻¹.

(39)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetylthiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 178° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620 cm⁻¹.

(40)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-pyrazinylthiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 174° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(41)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-thiazolin-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(42)7-[2-Methoxymino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3400, 3250, 1885, 1725, 1670, 1640, 1540 cm⁻¹.

(43)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 200° to 205° C. (dec.)

I.R. (Nujol): 3300, 1780, 1700, 1680, 1620, 1520 cm⁻¹.

(44)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-propyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(45)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-methoxypropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 167° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(46)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 178° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(47)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methoxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 174° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(48)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methylthiomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 173° to 175° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(49)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-propyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 182° to 184° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(50)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methylthiomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 178° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(51)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-isopropyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(52)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm⁻¹.

(53)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(2-hydroxyethyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(54)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-propyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 177° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

(55)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 170° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(56)7-[2-Methoxyimino-2(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methanesulfonamidomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(57)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-allylthio-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 173° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(58)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-mesylmethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(59) Sodium7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-sulfonatomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 205° to 210° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1530 cm⁻¹.

(60)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(61)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 185° to 190° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(62)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(3-methoxypropyl)-4H-1,2,4-triazol-3-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

(63)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(2-aminoethyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 205° to 210° C. (dec.)

I.R. (Nujol): 3200, 1770, 1670, 1620, 1530 cm⁻¹.

(64)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 210° to 215° C. (dec.)

I.R. (Nujol): 3350, 3200, 1770, 1680, 1620 cm⁻¹.

(65)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 200° to 205° C. (dec.)

I.R. (Nujol): 3350, 3200, 1775, 1670, 1620, 1530 cm⁻¹.

(66)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer). mp 140° to 156° C. (dec.)

I.R. (Nujol): 3370, 3250, 1780, 1730, 1680, 1620, 1530, 1380, 1240, 1040cm⁻¹.

(67)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 183° to 188° C. (dec.)

I.R. (Nujol): 3370, 3240, 1780, 1690, 1630, 1530, 1380, 1260, 1170, 1040cm⁻¹.

(68)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3360, 3240, 1780, 1690, 1630, 1530, 1375, 1250, 1170, 1040cm⁻¹.

(69)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 156° to 159° C. (dec.)

I.R. (Nujol): 3360, 3250, 1780, 1680, 1625, 1380, 1080, 1040 cm⁻¹.

(70)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 177° to 180° C. (dec.)

I.R. (Nujol): 3380, 3250, 1775, 1670, 1620, 1535, 1380, 1040 cm⁻¹.

(71)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.)

I.R. (Nujol): 3380, 3250, 1780, 1680, 1630, 1530, 1380, 1040 cm⁻¹.

(72)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3240, 1780, 1680, 1620, 1530, 1380, 1040 cm⁻¹.

(73)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 198° to 205° C. (dec.)

I.R. (Nujol): 3350, 3250, 1775, 1680, 1620, 1535, 1380, 1040 cm⁻¹.

(74)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 173° C. (dec.)

I.R. (Nujol): 3350, 3240, 1780, 1675, 1625, 1530, 1380, 1040, 720 cm⁻¹.

(75)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 185° to 190° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm⁻¹.

(76)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methoxycarbonyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1740, 1680, 1620, 1530 cm⁻¹.

(77)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-carboxy-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1730, 1680, 1620, 1530 cm⁻¹.

(78)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 182° to 185° C. (dec.).

I.R. (Nujol): 3350, 3200, 1770, 1670, 1620, 1530, 1380, 1040 cm⁻¹.

(79)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 195° to 210° C. (dec.).

I.R. (Nujol): 3340, 3210, 1770, 1675, 1620, 1530, 1380, 1040 cm⁻¹.

EXAMPLE 16

A mixture of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (3.5 g), pyrazinethiol (1.1 g) and sodium bicarbonate(1.3 g) in pH 6.86 phosphate buffer solution (150 ml) was stirred for 2hours at 70° C. The mixture was cooled in an ice bath, acidified with10% hydrochloric acid and extracted with ethyl acetate. The extract wasdried over magnesium sulfate and concentrated to 15 ml in vacuo. Aresulting precipitate was collected by filtration, washed with ethylacetate and dried to give crude7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-pyrazinylthiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.8 g). The crude product was dissolved in acetone,treated with activated charcoal powder and evaporated to dryness. Theresidue was dissolved in an aqueous solution of sodium bicarbonate andreprecipitated with an addition of 10% hydrochloric acid to give pureobject compound (1.1 g). mp 170° to 174° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.52 and 3.70 (2H, ABq, J=18 Hz), 3.97 (3H, s),4.05 and 4.57 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=4 Hz), 5.80 (1H, dd,J=4 and 8 Hz), 8.12 (2H, s), 8.3-8.6 (3H, m), 9.55 (1H, d, J=8 Hz).

EXAMPLE 17

A mixture of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (3.0 g), tetrazolo[1,5-b]pyridazine-6-thiol (1.3 g)and sodium bicarbonate (1.1 g) in pH 6.86 phosphate buffer solution (130ml) was stirred for 3 hours at 70° C. The mixture was cooled in an icebath, acidified to pH 2 with 10% hydrochloric acid and extracted withethyl acetate. The extract was dried over magnesium sulfate andconcentrated to 15 ml in vacuo. A resulting precipitate was collected byfiltration, washed with ethyl acetate and dried to give crude7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.5 g). The crude product was dissolved in aqueousacetone, treated with activated charcoal powder and evaporated todryness. The residue was dissolved in an aqueous solution of sodiumbicarbonate and reprecipitated with an addition of 10% hydrochloric acidto give pure object compound (1.15 g). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3400, 3250, 1885, 1725, 1670, 1640, 1540 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.62 and 3.82 (2H, ABq, J=18 Hz), 3.92 (3H, s),4.20 and 4.62 (2H, ABq, J=14 Hz), 5.14 (1H, d, J=4 Hz), 5.80 (1H, dd,J=4 and 8 Hz), 7.72 (1H, d, J=8 Hz), 8.10 (2H, s), 8.56 (1H, d, J=8 Hz),9.56 (1H, d, J=8 Hz).

EXAMPLE 18

A mixture of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (3.5 g),1-[2-(N-t-butoxycarbonylamino)ethyl]-1H-tetrazole-5-thiol (2.45 g) andsodium bicarbonate (1.3 g) in pH 6.86 phosphate buffer solution (150 ml)was stirred for 3 hours at 70° C. The mixture was cooled in an ice bath,washed with ethyl acetate, acidified to pH 2 with 10% hydrochloric acidand extracted with ethyl acetate. The extract was dried over magnesiumsulfate and concentrated to 10 ml in vacuo. A resulting precipitate wascollected by filtration, washed with ethyl acetate and diethyl ether anddried to give7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.0 g). mp 200° to 205° C. (dec.)

I.R. (Nujol): 3300, 1780, 1700, 1680, 1620, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (9H, s), 3.28 (2H, m), 3.63 (2H, broad s),3.87 (3H, s), 4.27 (4H, broad s), 5.07 (1H, d, J=4 Hz), 5.75 (1H, dd,J=4 and 8 Hz), 8.10 (2H, s), 9.50 (1H, d, J=8 Hz).

EXAMPLE 19

A mixture of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (3.5 g), sodium(5-mercapto-1H-tetrazol-1-yl)methanesulfonate (2.18 g) and sodiumbicarbonate (1.3 g) in pH 6.86 phosphate buffer solution (150 ml) wasstirred for 3 hours at 70° C. The mixture was cooled in an ice bath,adjusted to pH 3 with 10% hydrochloric acid and washed with ethylacetate. The aqueous solution was subjected to column chromatography onnon ion adsorption resin (Diaion HP 20) (Trademark: prepared byMitsubishi Chemical Industries). The column was washed with water andeluted with 30% aqueous methanol. The eluate was evaporated to removemethanol and then lyophilized to give sodium7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-sulfonatomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.67 g). mp 205° to 210° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.63 (2H, broad s), 3.88 (3H, s), 4.27 and 4.33(2H, ABq, J=14 Hz), 4.98 (2H, s), 5.07 (1H, d, J=4 Hz), 5.77 (1H, dd,J=4 and 8 Hz), 9.55 (1H, d, J=8 Hz).

EXAMPLE 20

A mixture of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (3.5 g), disodium (5-sulfido-1H-tetrazol-1-yl)acetate(2.0 g) and sodium bicarbonate (1.3 g) in pH 6.8 phosphate buffersolution (150 ml) was stirred for 3.5 hours at 70° C. The reactionmixture was cooled in an ice bath, mixed with ethyl acetate and adjustedto pH 3 with 10% hydrochloric acid. The aqueous layer was separated,mixed with ethyl acetate and the mixture was adjusted to pH 1 with 10%hydrochloric acid. The ethyl acetate layer was dried over magnesiumsulfate and evaporated to dryness. The residue was triturated withdiethyl ether to give7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.68 g), mp. 123° to 125° C. (dec.).

I.R. (Nujol): 3300, 3200, 1750, 1720, 1680, 1620, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.72 (2H, broad s), 3.97 (3H, s), 4.27 and 4.50(2H, ABq, J=13 Hz), 5.13 (1H, d, J=4 Hz), 5.33 (2H, s), 5.83 (1H, dd,J=4 and 8 Hz), 8.13 (2H, s), 9.60 (1H, d, J=8 Hz).

EXAMPLE 21

The following compounds were obtained according to similar manners tothose of Examples 16 to 20.

(1)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-thiazolin-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.43 (2H, m), 3.57 (2H, broad s), 3.93 (3H, s),4.0-4.5 (4H, m), 5.10 (1H, d, J=4 Hz), 5.80 (1H, dd, J=4 and 8 Hz), 8.10(2H, s), 9.50 (1H, d, J=8 Hz).

(2)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-propyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 0.83 (3H, t, J=7 Hz), 1.80 (2H, sextet, J=7 Hz),3.67 (2H, broad s), 3.92 (3H, s), 4.23 (2H, t, J=7 Hz), 4.35 (2H, broads), 5.08 (1H, d, J=4 Hz), 5.78 (1H, dd, J=4 and 8 Hz), 8.08 (2H, s),9.52 (1H, d, J=8 Hz).

(3)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-methoxypropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 167° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.02 (2H, quintet, J=7 Hz), 3.17 (3H, s), 3.30(2H, t, J=7 Hz), 3.67 (2H, broad s), 3.90 (3H, s), 4.32 (2H, t, J=7 Hz),4.35 (2H, broad s), 5.10 (1H, d, J=4 Hz), 5.80 (1H, dd, J=4 and 8 Hz),8.13 (2H, s), 9.57 (1H, d, J=8 Hz).

(4)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 178° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.58 (3H, s), 3.60 and 3.77 (2H, ABq, J=17 Hz),3.97 (3H, s), 4.30 and 4.63 (2H, ABq, J=14 Hz), 5.17 (1H, d, J=4 Hz),5.85 (1H, dd, J=4 and 8 Hz), 8.13 (2H, s), 9.57 (1H, d, J=8 Hz).

(5)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methoxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 174° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.40 (3H, s), 3.70 (2H, broad s), 3.93 (3H, s),4.27 and 4.70 (2H, ABq, J=13 Hz), 4.83 (2H, s), 5.17 (1H, d, J=4 Hz),5.83 (1H, dd, J=4 and 8 Hz), 8.12 (2H, s), 9.57 (1H, d, J=8 Hz).

(6)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methylthiomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 173° to 175° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.13 (3H, s), 3.70 (2H, broad s), 3.97 (3H, s),4.17 (2H, s), 4.27 and 4.57 (2H, ABq, J=14 Hz), 5.17 (1H, d, J=4 Hz),5.85 (1H, dd, J=4 and 8 Hz), 8.15 (2H, s), 9.58 (1H, d, J=8 Hz).

(7)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-propyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 182° to 184° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 0.83 (3H, t, J=7 Hz), 1.72 (2H, m), 3.67 (2H,broad s), 3.90 (2H, t, J=7 Hz), 3.93 (3H, s), 4.20 (2H, broad s), 5.10(1H, d, J=4 Hz), 5.80 (1H, dd, J=4 and 8 Hz), 8.12 (2H, s), 8.63 (1H,s), 9.57 (1H, d, J=8 Hz).

(8)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methylthiomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 178° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.17 (3H, s), 3.72 (2H, broad s), 3.93 (3H, s),4.30 and 4.50 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=4 Hz), 5.53 (2H, s),5.83 (1H, dd, J=4 and 8 Hz), 8.12 (2H, s), 9.57 (1H, d, J=8 Hz).

(9)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-isopropyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.48 (6H, d, J=6 Hz), 3.70 (2H, broad s), 3.93(3H, s), 4.43 (2H, broad, s), 4.75 (1H, m), 5.13 (1H, d, J=4 Hz), 5.82(1H, dd, J=4 and 8 Hz), 8.12 (2H, s), 9.57 (1H, d, J=8 Hz).

(10)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.67 (2H, broad s), 3.73 (2H, broad s), 3.90 (3H,s), 4.27 (2H, broad s), 4.33 (2H, broad s), 5.10 (1H, d, J=4 Hz), 5.80(1H, dd, J=4 and 8 Hz), 8.07 (2H, s), 9.53 (1H, d, J=8 Hz).

(11)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(2-hydroxyethyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.20 (2H, t, J=5 Hz), 3.67 (2H, broad s), 3.73(2H, t, J=5 Hz), 3.95 (3H, s), 4.27 and 4.57 (2H, ABq, J=13 Hz), 5.17(1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.13 (2H, s), 9.58 (1H, d,J=8 Hz).

(12)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-propyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 177° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 0.97 (3H, t, J=7 Hz), 1.73 (2H, m), 3.07 (2H, t,J=7 Hz), 3.70 (2H, broad s), 3.97 (3H, s), 4.37 and 4.57 (2H, ABq, J=13Hz), 5.17 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.13 (2H, s),9.57 (1H, d, J=8 Hz).

(13)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 170° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.67 (2H, broad s), 3.92 (3H, s), 4.27 and 4.57(2H, ABq, J=13 Hz), 4.82 (2H, s), 5.13 (1H, d, J=4 Hz), 5.83 (1H, dd,J=4 and 8 Hz), 8.17 (2H, s), 9.60 (1H, d, J=8 Hz).

(14)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methanesulfonamidomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.00 (3H, s), 3.67 (2H, broad s), 3.93 (3H, s),4.27 and 4.53 (2H, ABq, J=14 Hz), 4.55 (2H, d, J=6 Hz), 5.13 (1H, d, J=4Hz), 5.80 (1H, dd, J=4 and 8 Hz), 8.03 (1H, t, J=6 Hz), 8.10 (2H, s),9.53 (1H, d, J=8 Hz).

(15)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-allylthio-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 173° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.58 and 3.74 (2H, ABq, J=17 Hz), 3.90 (2H, d, J=6Hz), 3.92 (3H, s), 4.32 and 4.54 (2H, ABq, J=14 Hz), 5.15 (1H, d, J=4Hz), 5.0-5.4 (2H, m), 5.7-6.1 (1H, m), 5.84 (1H, dd, J=4 and 8 Hz), 8.12(2H, s), 9.58 (1H, d, J=8 Hz).

(16)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-mesylmethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.13 (3H, s), 3.70 (2H, broad s), 3.93 (3H, s),4.15 and 4.63 (2H, ABq, J=13 Hz), 5.17 (2H, s), 5.13 (1H, d, J=4 Hz),5.83 (1H, dd, J=4 and 8 Hz), 8.08 (2H, s), 9.53 (1H, d, J=8 Hz).

(17)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.53 (3H, s), 3.62 (2H, broad s), 3.87 (3H, s),4.08 (2H, broad s), 5.07 (1H, d, J=4 Hz), 5.75 (1H, dd, J=4 and 8 Hz),8.08 (2H, s), 8.52 (1H, s), 9.50 (1H, d, J=8 Hz).

(18)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 185° to 190° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.47 (6H, s), 3.0-3.3 (2H, m), 3.67 (2H, broad s),3.90 (3H, s), 4.28 (2H, broad s), 4.4-4.7 (2H, m), 5.08 (1H, d, J=4 Hz),5.77 (1H, dd, J=4 and 8 Hz), 8.12 (2H, s), 9.55 (1H, d, J=8 Hz).

(19)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(3-methoxypropyl)-4H-1,2,4-triazol-3-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.97 (2H, m), 3.28 (3H, s), 3.35 (2H, t, J=8 Hz),3.73 (2H, broad s), 3.97 (3H, s), 4.03 (2H, t, J=8 Hz), 4.23 (2H, broads), 5.17 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.15 (2H, s),8.67 (1H, s), 9.57 (1H, d, J=8 Hz).

(20)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(2-aminoethyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 205° to 210° C. (dec.)

I.R. (Nujol): 3200, 1770, 1670, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.10-3.70 (6H, m), 3.92 (3H, s), 4.50 (2H, broads), 5.06 (1H, d, J=4 Hz), 5.72 (1H, dd, J=4 and 8 Hz), 8.18 (2H, s),9.50 (1H, d, J=8 Hz).

(21)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 210° to 215° C. (dec.)

I.R. (Nujol): 3350, 3200, 1770, 1680, 1620 cm⁻¹.

(22)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 200° to 205° C. (dec.)

I.R. (Nujol): 3350, 3200, 1775, 1670, 1620, 1530 cm⁻¹.

(23)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 150° to 155° C. (dec.)

I.R. (Nujol): 3350, 3230, 1775, 1680, 1620, 1530 cm⁻¹.

(24)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 145° to 150° C. (dec.)

I.R. (Nujol): 3370, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

(25)7-[2-Propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 130° to 133° C. (dec.)

I.R. (Nujol): 3380, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

(26)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(N-t-butoxycarbonylamino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 150° to 155° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1670 cm⁻¹.

(27)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-allylthio-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.)

I.R (Nujol): 3350, 3250, 1780, 1680, 1620 cm⁻¹.

(28)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetylthiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp. 178° to 182° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620 cm⁻¹.

(29)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 183° to 188° C. (dec.)

I.R. (Nujol): 3370, 3240, 1780, 1690, 1630, 1530, 1380, 1260, 1170, 1040cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (3H, t, J=7 Hz), 1.38 (9H, s), 2.0 (2H, m),2.98 (2H, m), 3.7 (2H, m), 4.0-4.42 (6H, m), 5.17 (1H, d, J=4.5 Hz),5.83 (1H, dd, J=4.5 and 8.0 Hz), 6.83 (1H, m), 8.13 (2H, broad s), 9.53(1H, d, J=8.0 Hz).

(30)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3360, 3240, 1780, 1690, 1630, 1530, 1375, 1250, 1170, 1040cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (3H, t, J=7 Hz), 1.33 (9H, s), 3.17-4.0 (6H,m), 4.01-4.5 (4H, m), 5.17 (1H, d, J=4.5 Hz), 5.87 (1H, dd, J=4.5 and8.0 Hz), 7.0 (1H, m), 8.16 (2H, broad s), 9.57 (1H, d, J=8.0 Hz).

(31)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp. 156° to 159° C. (dec.)

I.R. (Nujol): 3360, 3250, 1780, 1680, 1625, 1380, 1080, 1040 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (3H, t, J=7 Hz), 3.7 (2H, broad s), 3.95 (3H,s), 4.0-4.56 (4H, m), 5.15 (1H, d, J=4.5 Hz), 5.83 (1H, dd, J=4.5 and 8Hz), 8.12 (2H, broad s), 9.53 (1H, d, J=8.0 Hz).

(32)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 177° to 180° C. (dec.)

I.R. (Nujol): 3380, 3250, 1775, 1670, 1620, 1535, 1380, 1040 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (3H, t, J=7 Hz), 2.50 (6H, s), 3.17 (2H, m),3.67 (2H, m), 4.22 (2H, q, J=7 Hz), 4.0-4.7 (4H, m), 5.13 (1H, d, J=4.5Hz), 5.83 (1H, dd, J=4.5 and 8.0 Hz), 8.17 (2H, broad s), 9.58 (1H, d,J=8.0 Hz).

(33)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.)

I.R. (Nujol): 3380, 3250, 1780, 1680, 1630, 1530, 1380, 1040 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.25 (3H, t, J=7 Hz), 3.7 (2H, m), 4.0-6.0 (13H,m), 8.13 (2H, broad s), 9.57 (1H, d, J=8.0 Hz).

(34)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3240, 1780, 1680, 1620, 1530, 1380, 1040 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (3H, t, J=7 Hz), 3.77 (2H, m), 4.20 (2H, q,J=7 Hz), 4.20 and 4.67 (2H, ABq, J=12 Hz), 5.20 (1H, d, J=4.5 Hz), 5.83(1H, dd, J=4.5 and 8 Hz), 7.73 (1H, d, J=9 Hz), 8.12 (2H, broad s), 8.56(1H, d, J=9 Hz), 9.53 (1H, d, J=8 Hz).

(35)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 198° to 205° C. (dec.)

I.R. (Nujol): 3350, 3250, 1775, 1680, 1620, 1535, 1380, 1040 cm⁻¹.

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.27 (3H, t, J=7 Hz), 3.6 (2H, broad s), 4.23(2H, q, J=7 Hz), 4.0-4.83 (4H, m), 5.13 (1H, d, J=4.5 Hz), 5.80 (1H, d,J=4.5 Hz).

(36)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 173° C. (dec.)

I.R. (Nujol): 3350, 3240, 1780, 1675, 1625, 1530, 1380, 1040, 720 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (3H, t, J=7 Hz), 3.67-4.4 (10H, m), 5.15 (1H,d, J=4.5 Hz), 5.83 (1H, dd, J=4.5 and 8 Hz), 8.13 (2H, broad s), 9.57(1H, d, J=8.0 Hz).

(37)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3cephem-4-carboxylicacid (syn isomer). mp 185° to 190° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.67 (2H, broad s), 3.93 (3H, s), 4.20 (2H, broads), 4.43-4.66 (2H, m), 4.88-5.40 (3H, m), 5.60-6.06 (2H, m), 8.18 (2H,s), 8.63 (1H, s), 9.57 (1H, d, J=8 Hz).

(38)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methoxycarbonyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1740, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 3.93 (6H, s), 4.47 (2H, broads), 5.17 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.10 (2H, s),9.57 (1H, d, J=8 Hz).

(39)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-carboxy-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1730, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.73 (2H, broad s), 3.93 (3H, s), 4.47 (2H, broads), 5.17 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.10 (2H, s),9.57 (1H, d, J=8 Hz).

(40)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 182° to 185° C. (dec.)

I.R. (Nujol): 3350, 3200, 1770, 1670, 1620, 1530, 1380, 1040 cm⁻¹.

(41)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 195° to 210° C. (dec.)

I.R. (Nujol): 3340, 3210, 1770, 1675, 1620, 1530, 1380, 1040 cm⁻¹.

(42)7-[2-(Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (6H, d, J=6 Hz), 3.67 (2H, broad s), 4.23 and4.47 (2H, ABq, J=14 Hz), 4.20-4.50 (1H, m), 5.10 (1H, d, J=4 Hz), 5.30(2H, s), 5.80 (1H, dd, J=4 and 8 Hz), 8.10 (2H, s), 9.47 (1H, d, J=8Hz).

(43)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-carboxymethylthio-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1720, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.60 and 3.72 (2H, ABq, J=18 Hz), 3.92 (3H, s),4.14 (2H, s), 4.22 and 4.48 (2H, ABq, J=14 Hz), 5.12 (1H, d, J=4 Hz),5.80 (1H, dd, J=4 and 8 Hz), 8.50 (2H, s), 9.50 (1H, d, J=8 Hz).

(44)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (6H, d, J=6 Hz), 3.73 (2H, broad s), 4.00(3H, s), 4.33 (2H, broad s), 4.27-4.67 (1H, m), 5.17 (1H, d, J=4 Hz),5.87 (1H, dd, J=4 and 8 Hz), 8.15 (2H, s), 9.53 (1H, d, J=8 Hz).

(45)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 142° to 147° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1690, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.22 (6H, d, J=6 Hz), 1.30 (9H, s), 3.17-3.50 (2H,m), 3.70 (2H, broad s), 4.17-4.57 (5H, m), 5.13 (1H, d, J=4 Hz), 5.83(1H, dd, J=4 and 8 Hz), 8.17 (2H, s), 9.55 (1H, d, J=8 Hz).

(46)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1710, 1670, 1625, 1525 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.23 (6H, d, J=6 Hz), 3.73 (2H, broad s),4.20-4.50 (1H, m), 4.25 and 4.62 (2H, ABq, J=13 Hz), 5.18 (1H, d, J=5Hz), 5.87 (1H, dd, J=5 and 8 Hz), 7.78 (1H, d, J=10 Hz), 8.18 (2H, broads), 8.63 (1H, d, J=10 Hz), 9.63 (1H, d, J=8 Hz).

(47)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 135° to 140° C. (dec.).

I.R. (Nujol): 3350, 3230, 1780, 1680, 1625, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (6H, d, J=6 Hz), 3.68 (2H, broad s), 4.25 and4.45 (2H, ABq, J=13 Hz), 4.20-4.50 (1H, m), 4.85-5.08 (2H, m), 5.13 (1H,d, J=5 Hz), 5.18-5.45 (2H, m), 5.82 (1H, dd, J=5 and 8 Hz), 5.60-6.20(1H, m), 8.12 (2H, broad s), 9.48 (1H, d, J=8 Hz).

(48)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 3.93 (3H, s), 4.37 and 4.65(2H, ABq, J=13 Hz), 5.17 (1H, d, J=5 Hz), 5.85 (1H, dd, J=5 and 8 Hz),8.17 (2H, broad s), 9.57 (1H, d, J=8 Hz).

(49)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-carboxymethyl-3-oxo-2,3-dihydro-1,2,4-triazolo[4,3-b]pyridiazin-6-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 205° to 210° C. (dec.).

I.R. (Nujol): 3300, 1765, 1710, 1680, 1620, 1550, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.67 (2H, broad s), 3.93 (3H, s), 4.27 (2H, broads), 4.63 (2H, s), 5.10 (1H, d, J=5 Hz), 5.75 (1H, dd, J=5 and 8 Hz),7.05 (1H, d, J=10 Hz), 7.67 (1H, d, J=10 Hz), 8.13 (2H, broad s), 9.53(1H, d, J=8 Hz).

(50)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methylamino-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3450, 3370, 3250, 1775, 1710, 1680, 1630, 1560 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.90 (3H, s), 3.68 (2H, broad s), 3.95 (3H, s),4.10 and 4.27 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=5 Hz), 5.83 (1H, dd,J=5 and 8 Hz), 7.83 (1H, broad s), 8.17 (2H, broad s), 9.60 (1H, d, J=8Hz).

(51)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-amino-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3350, 3210, 1770, 1670, 1620, 1520 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.67 (2H, broad s), 3.95 (3H, s), 4.08 and 4.25(2H, ABq, J=13 Hz), 5.12 (1H, d, J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz),7.33 (2H, broad s), 8.15 (2H, broad s), 9.57 (2H, d, J=8 Hz).

(52)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3370, 3250, 1785, 1690, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.37 (9H, s), 1.73-2.17 (2H, m), 2.73-3.17 (2H,m), 3.68 (2H, broad s), 3.90 (3H, s), 4.25 (2H, t, J=7 Hz), 4.27 (2H,broad s), 5.12 (1H, d, J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz), 6.70-7.02(1H, m), 8.13 (2H, broad s), 9.55 (1H, d, J=8 Hz).

(53)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(acetamido)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3230, 1780, 1660, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.80 (3H, s), 1.87-2.17 (2H, m), 2.90-3.30 (2H,m), 3.70 (2H, broad s), 3.93 (3H, s), 4.28 (2H, t, J=7 Hz), 4.30 (2H,broad s), 5.13 (1H, d, J=5 Hz), 5.82 (1H, dd, J=5 and 8 Hz), 7.77-8.03(1H, m), 8.10 (2H, broad s), 9.57 (1H, d, J=8 Hz).

(54)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(acetamidomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 160° to 165° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1660, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.52 (3H, d, J=6 Hz), 1.75 (3H, s), 3.13-3.80 (2H,m), 3.72 (2H, broad s), 3.93 (3H, s), 4.33 (2H, broad s), 4.50-4.83 (1H,m), 5.12 (1H, d, J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz), 8.00 (1H, t, J=6Hz), 8.10 (2H, broad s), 9.53 (1H, d, J=8 Hz).

(55)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(N-t-butoxycarbonylaminomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4carboxylicacid (syn isomer), mp. 180° to 185° C. (dec.).

I.R. (Nujol): 3370, 3230, 1780, 1690, 1630, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.33 (9H, s), 1.50 (3H, d, J=6 Hz), 3.17-3.60 (2H,m), 3.73 (2H, broad s), 3.93 (3H, s), 4.35 (2H, broad s), 4.33-4.83 (1H,m), 5.17 (1H, d, J-5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 6.93-7.23 (1H,m), 8.20 (2H, broad s), 9.72 (1H, d, J=8 Hz).

(56)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N,N-dimethylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3350, 3200, 1770, 1670, 1610, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 2.03-2.57 (2H, m), 2.67 (6H, s), 2.73-3.27 (2H,m), 3.67 (2H, broad s), 3.93 (3H, s), 4.33 (2H, broad s), 4.10-4.77 (2H,m), 5.05 (1H, d, J=5 Hz), 5.70 (1H, dd, J=5 and 8 Hz), 7.93-8.43 (3H,m), 9.53 (1H, d, J=8 Hz).

(57)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(N-t-butoxycarbonylamino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 1780, 1670, 1620, 1530 cm⁻¹.

(58)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3150, 1770, 1720, 1670, 1620, 1520 cm⁻¹.

(59)7-[2-Methoxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)acetamido-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 140° to 145° C. (dec.).

I.R. (Nujol): 3180, 1765, 1670, 1515 cm⁻¹.

(60)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 185° to 190° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1610, 1530 cm⁻¹.

(61)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 210° to 215° C. (dec.).

I.R. (Nujol): 3350, 3200, 1750, 1670, 1620, 1530 cm⁻¹.

(62)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 195° to 200° C. (dec.).

I.R. (Nujol): 3350, 3250, 1775, 1680, 1620, 1530 cm⁻¹.

(63)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(aminomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3350, 3230, 1770, 1670, 1620, 1530 cm⁻¹.

(64)7-[2-Methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 1780, 1680 cm⁻¹.

(65)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 1770, 1660, 1610, 1520 cm⁻¹.

(66)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3350, 1780, 1680, 1625, 1530 cm⁻¹.

(67)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 172° to 177° C. (dec.).

I.R. (Nujol): 3350, 1775, 1680, 1626, 1630 cm⁻¹.

(68)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 172° C. (dec.).

I.R. (Nujol): 3350, 1780, 1680, 1625, 1530 cm⁻¹.

EXAMPLE 22

A solution of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.0 g) in 99% formic acid (20 ml) was stirred for 2.5hours at ambient temperatures. The mixture was evaporated to dryness andthe residue was dissolved in an aqueous solution of sodium bicarbonateand adjusted to pH 3 with 10% hydrochloric acid. A resulting precipitatewas filtered off and the filtrate was subjected to column chromatographyon non ion adsorption resin (Dianion HP 20) (Trademark: prepared byMitsubishi Chemical Industries). The column was washed with water andeluted wth 50% aqueous methanol. The eluate was evaporated to removemethanol and then lyophilized to give7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (250 mg). mp 200° to 205° C. (dec.)

I.R. (Nujol): 3350, 3200, 1775, 1670, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.47 (2H, broad s), 3.60 (2H, broad s), 3.93 (3H,s), 4.2 (2H, broad s), 4.37 (2H, broad s), 4.78 (2H, broad s), 5.03 (1H,d, J=4 Hz), 5.70 (1H, dd, J=4 and 8 Hz), 8.10 (2H, s) 9.50 (1H, d, J=8Hz).

EXAMPLE 23

A solution of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.22 g) in formic acid (22 ml) was stirred for 2.5hours at ambient temperature. The reaction mixture was post-treated in aconventional manner to give7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.875 g), mp. 185° to 190° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1610, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO+D₂ O, δ): 2.0-2.33 (2H, m), 2.67-3.0 (2H, m), 3.40-3.70(2H, m), 3.93 (3H, s), 4.10-4.67 (4H, m), 5.03 (1H, d, J=5 Hz), 5.75(1H, d, J=5 Hz).

EXAMPLE 24

The following compounds were obtained according to similar manners tothose of Examples 22 and 23.

(1)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 210°-215° C. (dec.)

I.R. (Nujol): 3350, 3200, 1770, 1680, 1620 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 3.60 (2H, broad s), 3.93 (3H, s), 4.33 and 4.57(2H, ABq, J=13 Hz), 4.43 (2H, s), 5.10 (1H, d, J=4 Hz), 5.77 (1H, dd,J=4 and 8 Hz), 8.17 (2H, s), 9.50 (1H, d, J=8 Hz).

(2)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(2-aminoethyl)1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 205° to 210° C. (dec.)

I.R. (Nujol): 3200, 1770, 1670, 1620, 1530 cm⁻¹.

(3)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 198° to 205° C. (dec.)

I.R. (Nujol): 3350, 3250, 1775, 1680, 1620, 1535, 1380, 1040 cm⁻¹.

(4)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 182° to 185° C. (dec.)

I.R. (Nujol): 3350, 3200, 1770, 1670, 1620, 1530, 1380, 1040 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (3H, t, J=7 Hz), 2.17 (2H, m), 2.83 (2H, m),4.17 (2H, q, J=7 Hz), 3.7-4.7 (6H, m), 5.00 (1H, d, J=4.5 Hz), 5.70 (1H,dd, J=4.5 and 8.0 Hz), 8.17 (2H, broad s), 9.33 (1H, d, J=8.0 Hz).

(5)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 195° to 210° C. (dec.)

I.R. (Nujol): 3340, 3210, 1770, 1675, 1620, 1530, 1380, 1040 cm⁻¹.

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.26 (3H, t, J=7 Hz), 3.0-3.7 (4H, m),4.0-4.5 (4H, m), 4.66 (2H, m), 5.03 (1H, d, J=4.5 Hz), 5.70 (1H, d,J=4.5 Hz).

(6)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 210° to 215° C. (dec.).

I.R. (Nujol): 3350, 3200, 1750, 1670, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.30 (6H, d, J=6 Hz), 3.67 (2H, broad s),4.20-4.83 (5H, m), 5.13 (1H, d, J=4 Hz), 5.80 (1H, dd, J=4 and 8 Hz),8.13 (2H, s), 9.43 (1H, d, J=8 Hz).

(7)7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 195° to 200° C. (dec.).

I.R. (Nujol): 3350, 3250, 1775, 1680, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO, δ): 1.27 (6H, d, J=6 Hz), 3.47 (2H, broad s), 3.67(2H, broad s), 4.27 (2H, broad s), 4.33-4.57 (1H, m), 4.67 (2H, broads), 5.10 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.17 (2H, s),9.47 (1H, d, J=8 Hz).

(8)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{1-(aminomethyl)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3350, 3230, 1770, 1670, 1620, 1530 cm⁻¹.

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.23-1.70 (3H, m), 3.10-3.80 (4H, m), 3.92(3H, s), 4.0-4.5 (3H, m), 5.05 (1H, d, J=5 Hz), 5.73 (1H, d, J=5 Hz).

(9)7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-amino-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3350, 3210, 1770, 1670, 1620, 1520 cm⁻¹.

What we claim is:
 1. A compound of the formula ##STR15## wherein R¹ isamino or a protected amino andR² is lower alkyl,and its reactivederivative at the carboxy group selected from the group consisting ofacid halide, acid anhydride, acid azide, amide and ester, and saltthereof.
 2. Syn isomer of a compound of claim 1, wherein the reactivederivative at the carboxy group is acid halide.
 3. A compound of claim2, wherein R¹ is amino.
 4. A compound of claim 2, wherein R¹ is loweralkanoylamino.
 5. A compound of claim 3, wherein R² is methyl, ethyl,propyl or isopropyl.
 6. A compound of claim 5, which is2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer).
 7. A compound of claim 5, which is2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer).8. A compound of claim 5, which is2-propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer).
 9. A compound of claim 5, which is2-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer).